Johansson, M. E., Sjovall, H. & Hansson, G. C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361, (2013).
Google Scholar
Holmgren, J. & Czerkinsky, C. Mucosal immunity and vaccines. Nat. Med. 11, S45–S53 (2005).
Google Scholar
Steele, L., Mayer, L. & Berin, M. C. Mucosal immunology of tolerance and allergy in the gastrointestinal tract. Immunol. Res. 54, 75–82 (2012).
Google Scholar
Chistiakov, D. A. et al. Intestinal mucosal tolerance and impact of gut microbiota to mucosal tolerance. Front. Microbiol. 5, 781 (2014).
Google Scholar
Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
Google Scholar
Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020).
Google Scholar
Lamers, M. M. et al. SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50–54 (2020).
Google Scholar
Bojkova, D. et al. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovasc. Res. 116, 2207–2215 (2020).
Google Scholar
Diao, B. et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection. Nat. Commun. 12, 2506 (2021).
Google Scholar
Wanner, N. et al. Molecular consequences of SARS-CoV-2 liver tropism. Nat. Metab. 4, 310–319 (2022).
Google Scholar
Cheung, K. S. et al. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong cohort: systematic review and meta-analysis. Gastroenterology 159, 81–95 (2020).
Google Scholar
Frazier, K. M., Hooper, J. E., Mostafa, H. H. & Stewart, C. M. SARS-CoV-2 virus isolated from the mastoid and middle ear: implications for COVID-19 precautions during ear surgery. JAMA Otolaryngol. Head. Neck Surg. 146, 964–966 (2020).
Google Scholar
Jeong, G. U. et al. Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation. Nat. Commun. 13, 7675 (2022).
Google Scholar
Song, E. et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 218, e20202135 (2021).
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e278 (2020).
Google Scholar
Yao, X. H. et al. Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient. Cell Res. 30, 541–543 (2020).
Google Scholar
Deshmukh, V. et al. Histopathological observations in COVID-19: a systematic review. J. Clin. Pathol. 74, 76–83 (2021).
Google Scholar
Huang, Y. et al. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharm. Sin. 41, 1141–1149 (2020).
Google Scholar
Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409–424 (2021).
Google Scholar
Magazine, N. et al. Mutations and evolution of the SARS-CoV-2 spike protein. Viruses. 14, 640 (2022).
Planas, D. et al. Reduced sensitivity of SARS-CoV-2 variant delta to antibody neutralization. Nature 596, 276–280 (2021).
Google Scholar
Plante, J. A. et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature 592, 116–121 (2021).
Google Scholar
Santa Cruz, A. et al. Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8(+)beta7 integrin(+) T cells and anti-SARS-CoV-2 IgA response. Nat. Commun. 14, 1772 (2023).
Google Scholar
Ma, X. et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Cell Mol. Immunol. 18, 487–489 (2021).
Google Scholar
Liu, D. et al. Evaluation of the presence of SARS-CoV-2 in vaginal and anal swabs of women with omicron variants of SARS-CoV-2 infection. Front. Microbiol. 13, 1035359 (2022).
Google Scholar
Birchenough, G. M. et al. New developments in goblet cell mucus secretion and function. Mucosal Immunol. 8, 712–719 (2015).
Google Scholar
Cesta, M. F. Normal structure, function, and histology of mucosa-associated lymphoid tissue. Toxicol. Pathol. 34, 599–608 (2006).
Google Scholar
Breslin, J. W. et al. Lymphatic vessel network structure and physiology. Compr. Physiol. 9, 207–299 (2018).
Google Scholar
Lehmann, M. et al. Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8(+) T cells. Mucosal Immunol. 14, 1381–1392 (2021).
Google Scholar
Cheemarla, N. R. et al. Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics. J. Exp. Med. 218, e20210583 (2021).
Google Scholar
Loske, J. et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat. Biotechnol. 40, 319–324 (2022).
Google Scholar
Debertin, A. S. et al. Nasal-associated lymphoid tissue (NALT): frequency and localization in young children. Clin. Exp. Immunol. 134, 503–507 (2003).
Google Scholar
Kiyono, H. & Fukuyama, S. NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4, 699–710 (2004).
Google Scholar
Isaacson, G. & Parikh, T. Developmental anatomy of the tonsil and its implications for intracapsular tonsillectomy. Int. J. Pediatr. Otorhinolaryngol. 72, 89–96 (2008).
Google Scholar
Ogasawara, N. et al. Epithelial barrier and antigen uptake in lymphoepithelium of human adenoids. Acta Otolaryngol. 131, 116–123 (2011).
Google Scholar
Bauer, I. et al. Adenoid as a source of lymphocytes in the surface secretions of nasopharynx. Int. J. Pediatr. Otorhinolaryngol. 72, 321–326 (2008).
Google Scholar
Boyaka, P. N. et al. Human nasopharyngeal-associated lymphoreticular tissues. Functional analysis of subepithelial and intraepithelial B and T cells from adenoids and tonsils. Am. J. Pathol. 157, 2023–2035 (2000).
Google Scholar
Zeng, G., Zhang, G. & Chen, X. Th1 cytokines, true functional signatures for protective immunity against TB? Cell Mol. Immunol. 15, 206–215 (2018).
Google Scholar
Ivarsson, M. & Lundin, B. S. Cytokines produced by T cells in adenoid surface secretion are mainly downregulatory or of Th1 type. Acta Otolaryngol. 126, 186–190, (2006).
Google Scholar
Dardalhon, V., Korn, T., Kuchroo, V. K. & Anderson, A. C. Role of Th1 and Th17 cells in organ-specific autoimmunity. J. Autoimmun. 31, 252–256, (2008).
Google Scholar
Walker, J. A. & McKenzie, A. N. J. T(H)2 cell development and function. Nat. Rev. Immunol. 18, 121–133 (2018).
Google Scholar
Belcher, R. & Virgin, F. The role of the adenoids in pediatric chronic rhinosinusitis. Med. Sci. 7, 35 (2019).
Huang, S. W. & Giannoni, C. The risk of adenoid hypertrophy in children with allergic rhinitis. Ann. Allergy Asthma Immunol. 87, 350–355, (2001).
Google Scholar
Gil-Etayo, F. J. et al. T-helper cell subset response is a determining factor in COVID-19 progression. Front. Cell Infect. Microbiol. 11, 624483 (2021).
Google Scholar
Nakamura, T., Kamogawa, Y., Bottomly, K. & Flavell, R. A. Polarization of IL-4- and IFN-gamma-producing CD4+ T cells following activation of naive CD4+ T cells. J. Immunol. 158, 1085–1094, (1997).
Google Scholar
Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991).
Google Scholar
Kidd, P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alter. Med. Rev. 8, 223–246, (2003).
Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456, (2011).
Google Scholar
Ribot, J. C., Lopes, N. & Silva-Santos, B. Gamma delta T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021).
Google Scholar
Olofsson, K., Hellstrom, S. & Hammarstrom, M. L. Abundance of intraepithelial gamma delta T cells in hypertrophic obstructive but not in chronically infected adenoids. Clin. Exp. Immunol. 106, 396–403 (1996).
Google Scholar
Kalyan, S. & Kabelitz, D. When neutrophils meet T cells: beginnings of a tumultuous relationship with underappreciated potential. Eur. J. Immunol. 44, 627–633, (2014).
Google Scholar
Gay, L. et al. Vgamma9Vdelta2 T-cells are potent inhibitors of SARS-CoV-2 replication and represent effector phenotypes in patients with COVID-19. J. Infect. Dis. 229, 1759–1769 (2024).
Google Scholar
Alexandrova, Y., Costiniuk, C. T. & Jenabian, M. A. Pulmonary immune dysregulation and viral persistence during HIV infection. Front. Immunol. 12, 808722 (2021).
Google Scholar
Lei, L. et al. The phenotypic changes of gammadelta T cells in COVID-19 patients. J. Cell Mol. Med. 24, 11603–11606 (2020).
Google Scholar
von Massow, G., Oh, S., Lam, A. & Gustafsson, K. Gamma Delta T cells and their involvement in COVID-19virus infections. Front. Immunol. 12, 741218 (2021).
Google Scholar
Ivarsson, M., Lundin, B. S. & Lundberg, C. Activated T cells in the surface secretion on the adenoid-a flow cytometric study. Scand. J. Immunol. 56, 310–314, (2002).
Google Scholar
Mizrahi, S. et al. A phenotypic and functional characterization of NK cells in adenoids. J. Leukoc. Biol. 82, 1095–1105 (2007).
Google Scholar
Ferlazzo, G. & Munz, C. NK cell compartments and their activation by dendritic cells. J. Immunol. 172, 1333–1339, (2004).
Google Scholar
Zhu, Y. et al. Adenoid lymphocyte heterogeneity in pediatric adenoid hypertrophy and obstructive sleep apnea. Front. Immunol. 14, 1186258 (2023).
Google Scholar
Vivier, E. et al. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).
Google Scholar
Zeidler, R. et al. Rapid proliferation of B cells from adenoids in response to Epstein-Barr virus infection. Cancer Res. 56, 5610–5614 (1996).
Google Scholar
Morita, R. et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108–121 (2011).
Google Scholar
Morris, M. C. et al. Adenoidal follicular T helper cells provide stronger B-cell help than those from tonsils. Laryngoscope 126, E80–E85 (2016).
Google Scholar
Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).
Google Scholar
Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).
Google Scholar
Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).
Google Scholar
Xu, Q. et al. Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children. Nat. Immunol. 24, 186–199 (2023).
Google Scholar
Mettelman, R. C., Allen, E. K. & Thomas, P. G. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 55, 749–780 (2022).
Google Scholar
Button, B. et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337, 937–941 (2012).
Google Scholar
Ahn, J. H. et al. Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19. J. Clin. Investig. 131, e148517 (2021).
Google Scholar
Wu, C. T. et al. SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming. Cell 186, 112–130.e120 (2023).
Google Scholar
Lee, I. T. et al. ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nat. Commun. 11, 5453 (2020).
Google Scholar
Nakayama, T. et al. Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers. Cell Rep. Med. 2, 100421 (2021).
Google Scholar
Meinhardt, J. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat. Neurosci. 24, 168–175 (2021).
Google Scholar
Finlay, J. B. et al. Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium. Sci. Transl. Med. 14, eadd0484 (2022).
Google Scholar
Zhang, B. Z. et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 30, 928–931 (2020).
Google Scholar
Crunfli, F. et al. Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc. Natl. Acad. Sci. USA 119, e2200960119 (2022).
Google Scholar
Martinez-Marmol, R. et al. SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity. Sci. Adv. 9, eadg2248 (2023).
Google Scholar
Mesci, P. et al. SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir. PLoS Biol. 20, e3001845 (2022).
Google Scholar
Nabizadeh, F. et al. Autoimmune encephalitis associated with COVID-19: a systematic review. Mult. Scler. Relat. Disord. 62, 103795 (2022).
Google Scholar
Dunkelberger, J. R. & Song, W. C. Complement and its role in innate and adaptive immune responses. Cell Res. 20, 34–50 (2010).
Google Scholar
Ma, L. et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci. Immunol. 6, eabh2259 (2021).
Google Scholar
Yu, J. et al. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood 136, 2080–2089 (2020).
Google Scholar
Satyam, A. et al. Activation of classical and alternative complement pathways in the pathogenesis of lung injury in COVID-19. Clin. Immunol. 226, 108716 (2021).
Google Scholar
Ali, Y. M. et al. Lectin pathway mediates complement activation by SARS-CoV-2 proteins. Front. Immunol. 12, 714511 (2021).
Google Scholar
Holter, J. C. et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc. Natl. Acad. Sci. USA 117, 25018–25025 (2020).
Google Scholar
Sinkovits, G. et al. Complement overactivation and consumption predicts in-hospital mortality in SARS-CoV-2 Infection. Front. Immunol. 12, 663187 (2021).
Google Scholar
Shen, B. et al. Proteomic and metabolomic characterization of COVID-19 patient Sera. Cell 182, 59–72.e15 (2020).
Google Scholar
Ramlall, V. et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat. Med. 26, 1609–1615 (2020).
Google Scholar
Mastaglio, S. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin. Immunol. 215, 108450 (2020).
Google Scholar
Laurence, J. et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin. Immunol. 219, 108555 (2020).
Google Scholar
Moon, R. et al. Complement C3 production in human intestinal epithelial cells is regulated by interleukin 1beta and tumor necrosis factor alpha. Arch. Surg. 132, 1289–1293, (1997).
Google Scholar
Varsano, S., Kaminsky, M., Kaiser, M. & Rashkovsky, L. Generation of complement C3 and expression of cell membrane complement inhibitory proteins by human bronchial epithelium cell line. Thorax 55, 364–369, (2000).
Google Scholar
Chaudhary, N. et al. A single-cell lung atlas of complement genes identifies the mesothelium and epithelium as prominent sources of extrahepatic complement proteins. Mucosal Immunol. 15, 927–939 (2022).
Google Scholar
Leaker, B. R. et al. The nasal mucosal late allergic reaction to grass pollen involves type 2 inflammation (IL-5 and IL-13), the inflammasome (IL-1beta), and complement. Mucosal Immunol. 10, 408–420 (2017).
Google Scholar
Linden, S. K. et al. Mucins in the mucosal barrier to infection. Mucosal Immunol. 1, 183–197 (2008).
Google Scholar
Kousathanas, A. et al. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature 607, 97–103 (2022).
Google Scholar
Rebendenne, A. et al. Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Nat. Genet. 54, 1090–1102 (2022).
Google Scholar
Smet, A. et al. A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity. JCI Insight 6, e151777 (2021).
Google Scholar
Biering, S. B. et al. Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection. Nat. Genet 54, 1078–1089 (2022).
Google Scholar
Zhang, Q. et al. A database of anti-coronavirus peptides. Sci. Data 9, 294 (2022).
Google Scholar
Wang, C. et al. Human Intestinal Defensin 5 Inhibits SARS-CoV-2 Invasion by Cloaking ACE2. Gastroenterology 159, 1145–1147 e1144 (2020).
Google Scholar
Zhao, H. J. et al. A trifunctional peptide broadly inhibits SARS-CoV-2 Delta and Omicron variants in hamsters. Cell Discov. 8, 62 (2022).
Zhang, R. et al. Antimicrobial peptide DP7 with potential activity against SARS coronavirus infections. Signal. Transduct. Target Ther. 6, 140 (2021).
Google Scholar
Ghosh, S. K. & Weinberg, A. Ramping up antimicrobial peptides against severe acute respiratory syndrome Coronavirus-2. Front. Mol. Biosci. 8, 620806 (2021).
Google Scholar
Casadei, E. & Salinas, I. Comparative models for human nasal infections and immunity. Dev. Comp. Immunol. 92, 212–222 (2019).
Google Scholar
Tacchi, L. et al. Nasal immunity is an ancient arm of the mucosal immune system of vertebrates. Nat. Commun. 5, 5205 (2014).
Google Scholar
Sepahi, A. & Salinas, I. The evolution of nasal immune systems in vertebrates. Mol. Immunol. 69, 131–138 (2016).
Google Scholar
Sepahi, A. et al. Tissue Microenvironments in the Nasal Epithelium of Rainbow Trout (Oncorhynchus mykiss) define two distinct CD8α+ cell populations and establish regional immunity. J. Immunol. 197, 4453–4463 (2016).
Google Scholar
Das, P. K. & Salinas, I. Fish nasal immunity: from mucosal vaccines to neuroimmunology. Fish. Shellfish Immunol. 104, 165–171 (2020).
Google Scholar
Garcia, B. et al. A novel organized Nasopharynx-Associated Lymphoid tissue in Teleosts that expresses molecular markers characteristic of mammalian germinal centers. J. Immunol. 209, 2215–2226 (2022).
Google Scholar
Heritage, P. L. et al. Comparison of murine nasal-associated lymphoid tissue and Peyer’s patches. Am. J. Respir. Crit. Care Med. 156, 1256–1262 (1997).
Google Scholar
Csencsits, K. L., Jutila, M. A. & Pascual, D. W. Nasal-associated lymphoid tissue: phenotypic and functional evidence for the primary role of peripheral node addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site. J. Immunol. 163, 1382–1389 (1999).
Google Scholar
Hiroi, T. et al. Nasal immune system: distinctive Th0 and Th1/Th2 type environments in murine nasal-associated lymphoid tissues and nasal passage, respectively. Eur. J. Immunol. 28, 3346–3353 (1998).
Google Scholar
Lee, H. et al. Phenotype and function of nasal dendritic cells. Mucosal Immunol. 8, 1083–1098 (2015).
Google Scholar
Pabst, R. Mucosal vaccination by the intranasal route. Nose-associated lymphoid tissue (NALT)-Structure, function and species differences. Vaccine 33, 4406–4413 (2015).
Google Scholar
Hartmann, E. et al. Analysis of plasmacytoid and myeloid dendritic cells in nasal epithelium. Clin. Vaccin. Immunol. 13, 1278–1286 (2006).
Google Scholar
Collin, M. & Bigley, V. Human dendritic cell subsets: an update. Immunology 154, 3–20 (2018).
Google Scholar
Diebold, S. S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003).
Google Scholar
Zuercher, A. W. et al. Nasal-associated lymphoid tissue is a mucosal inductive site for virus-specific humoral and cellular immune responses. J. Immunol. 168, 1796–1803 (2002).
Google Scholar
Tay, M. Z. et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020).
Google Scholar
Zhu, F. et al. H1N1 influenza virus-infected nasal mucosal epithelial progenitor cells promote dendritic cell recruitment and maturation. Front. Immunol. 13, 879575 (2022).
Google Scholar
Yoshida, M. et al. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature 602, 321–327 (2022).
Google Scholar
Dillon, A. & Lo, D. D. M Cells: intelligent engineering of mucosal immune surveillance. Front. Immunol. 10, 1499 (2019).
Google Scholar
Shimoda, M. et al. Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue. J. Exp. Med. 194, 1597–1607, (2001).
Google Scholar
Marking, U. et al. 7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection. Lancet Infect. Dis. 23, 150–152 (2023).
Google Scholar
Sealy, R., Jones, B. G., Surman, S. L. & Hurwitz, J. L. Robust IgA and IgG-producing antibody forming cells in the diffuse-NALT and lungs of Sendai virus-vaccinated cotton rats associate with rapid protection against human parainfluenza virus-type 1. Vaccine 28, 6749–6756, (2010).
Google Scholar
Liang, B., Hyland, L. & Hou, S. Nasal-associated lymphoid tissue is a site of long-term virus-specific antibody production following respiratory virus infection of mice. J. Virol. 75, 5416–5420, (2001).
Google Scholar
Oh, J. E. et al. Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA. Sci. Immunol. 6, eabj5129 (2021).
Google Scholar
Tiboni, M., Casettari, L. & Illum, L. Nasal vaccination against SARS-CoV-2: synergistic or alternative to intramuscular vaccines? Int. J. Pharm. 603, 120686 (2021).
Google Scholar
Van der Ley, P. & Schijns, V. E. Outer membrane vesicle-based intranasal vaccines. Curr. Opin. Immunol. 84, 102376 (2023).
Google Scholar
Lobaina Mato, Y. Nasal route for vaccine and drug delivery: features and current opportunities. Int. J. Pharm. 572, 118813 (2019).
Google Scholar
Fu, W. et al. Injectable hydrogel mucosal vaccine elicits protective immunity against respiratory viruses. ACS Nano 18, 11200–11216 (2024).
Google Scholar
Zhang, H. et al. Intranasal G5-BGG/pDNA vaccine elicits protective systemic and mucosal immunity against SARS-CoV-2 by transfecting mucosal dendritic cells. Adv. Health. Mater. 13, e2303261 (2024).
Google Scholar
Bustamante-Marin, X. M. & Ostrowski, L. E. Cilia and Mucociliary Clearance. Cold Spring Harb. Perspect. Biol. 9, a028241 (2017).
Han, S. & Mallampalli, R. K. The role of surfactant in lung disease and host defense against pulmonary infections. Ann. Am. Thorac. Soc. 12, 765–774, (2015).
Google Scholar
Braciale, T. J., Sun, J. & Kim, T. S. Regulating the adaptive immune response to respiratory virus infection. Nat. Rev. Immunol. 12, 295–305 (2012).
Google Scholar
Wong, M. H. & Johnson, M. D. Differential response of primary alveolar type I and type II cells to LPS stimulation. PLoS ONE 8, e55545 (2013).
Google Scholar
Guillot, L. et al. Alveolar epithelial cells: master regulators of lung homeostasis. Int. J. Biochem. Cell Biol. 45, 2568–2573 (2013).
Google Scholar
Carcaterra, M. & Caruso, C. Alveolar epithelial cell type II as main target of SARS-CoV-2 virus and COVID-19 development via NF-Kb pathway deregulation: a physio-pathological theory. Med. Hypotheses 146, 110412 (2021).
Google Scholar
Valyaeva, A. A. et al. Expression of SARS-CoV-2 entry factors in lung epithelial stem cells and its potential implications for COVID-19. Sci. Rep. 10, 17772 (2020).
Google Scholar
Chen, H. et al. SARS-CoV-2 activates lung epithelial cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients. EBioMedicine 70, 103500 (2021).
Google Scholar
Upadhya, S., Rehman, J., Malik, A. B. & Chen, S. Mechanisms of lung injury induced by SARS-CoV-2 infection. Physiology 37, 88–100 (2022).
Google Scholar
Polidoro, R. B., Hagan, R. S., de Santis Santiago, R. & Schmidt, N. W. Overview: systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection explains severe outcomes in COVID-19. Front. Immunol. 11, 2020 (1626).
Lv, J. et al. ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques. Cell Mol. Immunol. 18, 1308–1310 (2021).
Google Scholar
Liu, Y. et al. Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19. Cell Res. 30, 1078–1087 (2020).
Google Scholar
Lv, J. et al. Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages. Cell Discov. 7, 24 (2021).
Google Scholar
Zhao, M. M. et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal. Transduct. Target Ther. 6, 134 (2021).
Google Scholar
Meyer, N. J., Gattinoni, L. & Calfee, C. S. Acute respiratory distress syndrome. Lancet 398, 622–637 (2021).
Google Scholar
Ikeo, S. et al. Negative pressure pulmonary edema in a patient with COVID-19. Respirol. Case Rep. 10, e01062 (2022).
Google Scholar
George, P. M., Wells, A. U. & Jenkins, R. G. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir. Med. 8, 807–815 (2020).
Google Scholar
Wendisch, D. et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 184, 6243–6261.e6227 (2021).
Google Scholar
Wu, J. et al. CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis. Signal. Transduct. Target Ther. 7, 382 (2022).
Google Scholar
Sriwilaijaroen, N. & Suzuki, Y. Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 88, 226–249, (2012).
Google Scholar
Lakdawala, S. S. et al. The soft palate is an important site of adaptation for transmissible influenza viruses. Nature 526, 122–125 (2015).
Google Scholar
Kolkhir, P. et al. Type 2 chronic inflammatory diseases: targets, therapies and unmet needs. Nat. Rev. Drug Discov. 22, 743–767 (2023).
Google Scholar
Teijaro, J. R. et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 146, 980–991 (2011).
Google Scholar
Kalil, A. C. & Thomas, P. G. Influenza virus-related critical illness: pathophysiology and epidemiology. Crit. Care 23, 258 (2019).
Google Scholar
Ehrt, S., Schnappinger, D. & Rhee, K. Y. Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis. Nat. Rev. Microbiol 16, 496–507 (2018).
Google Scholar
Luies, L. & du Preez, I. The echo of pulmonary tuberculosis: mechanisms of clinical symptoms and other disease-induced systemic complications. Clin. Microbiol. Rev. 33, 10–1128 (2020).
Quigley, J. et al. The cell wall lipid PDIM contributes to phagosomal escape and host cell exit of mycobacterium tuberculosis. mBio. 8, 10–1128 (2017).
Fratti, R. A., Chua, J., Vergne, I. & Deretic, V. Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Proc. Natl Acad. Sci. USA 100, 5437–5442, (2003).
Google Scholar
Vergne, I. et al. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 4033–4038 (2005).
Google Scholar
Bach, H. et al. Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe 3, 316–322 (2008).
Google Scholar
Cowley, S. et al. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol. Microbiol. 52, 1691–1702 (2004).
Google Scholar
Akkaya, M., Kwak, K. & Pierce, S. K. B cell memory: building two walls of protection against pathogens. Nat. Rev. Immunol. 20, 229–238 (2020).
Google Scholar
Lucas, C. et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat. Med. 27, 1178–1186 (2021).
Google Scholar
Zervou, F. N. et al. SARS-CoV-2 antibodies: IgA correlates with severity of disease in early COVID-19 infection. J. Med. Virol. 93, 5409–5415 (2021).
Google Scholar
Wajnberg, A. et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science 370, 1227–1230 (2020).
Google Scholar
Turula, H. & Wobus, C. E. The role of the polymeric immunoglobulin receptor and secretory immunoglobulins during mucosal infection and immunity. Viruses 10, 237 (2018).
Google Scholar
Zhao, J. et al. Antibody responses to SARS-CoV-2 in patients with novel Coronavirus Disease 2019. Clin. Infect. Dis. 71, 2027–2034 (2020).
Google Scholar
Guo, L. et al. Profiling early humoral response to diagnose Novel Coronavirus Disease (COVID-19). Clin. Infect. Dis. 71, 778–785 (2020).
Google Scholar
Xu, Z. et al. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat. Rev. Immunol. 12, 517–531 (2012).
Google Scholar
Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu Rev. Immunol. 26, 261–292, (2008).
Google Scholar
Sorensen, V. et al. Structural requirements for incorporation of J chain into human IgM and IgA. Int. Immunol. 12, 19–27 (2000).
Google Scholar
Wang, Z. et al. Enhanced SARS-CoV-2 neutralization by dimeric IgA. Sci. Transl. Med. 13, eabf1555 (2021).
Google Scholar
Svilenov, H. L. et al. Multimeric ACE2-IgM fusions as broadly active antivirals that potently neutralize SARS-CoV-2 variants. Commun. Biol. 5, 1237 (2022).
Google Scholar
Mantis, N. J., Rol, N. & Corthesy, B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 4, 603–611, (2011).
Google Scholar
Blandino, R. & Baumgarth, N. Secreted IgM: new tricks for an old molecule. J. Leukoc. Biol. 106, 1021–1034 (2019).
Google Scholar
Montague, B. T. et al. Anti-SARS-CoV-2 IgA identifies asymptomatic infection in first responders. J. Infect. Dis. 225, 578–586 (2022).
Google Scholar
Reinwald, M. et al. Prevalence and course of IgA and IgG antibodies against SARS-CoV-2 in healthcare workers during the first wave of the COVID-19 outbreak in germany: interim results from an ongoing observational cohort study. Healthcare. 9, 498 (2021).
Cervia, C. et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J. Allergy Clin. Immunol. 147, 545–557.e549 (2021).
Google Scholar
Soffritti, I. et al. Evaluation of anti-SARS-CoV-2 IgA response in tears of vaccinated COVID-19 subjects. Viruses 15, 399 (2023).
Google Scholar
Valcarce, V. et al. Detection of SARS-CoV-2-Specific IgA in the Human Milk of COVID-19 vaccinated lactating health care workers. Breastfeed. Med. 16, 1004–1009 (2021).
Google Scholar
Britton, G. J. et al. Limited intestinal inflammation despite diarrhea, fecal viral RNA and SARS-CoV-2-specific IgA in patients with acute COVID-19. Sci. Rep. 11, 13308 (2021).
Google Scholar
Sterlin, D. et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci. Transl. Med. 13, eabd2223 (2021).
Sano, K. et al. SARS-CoV-2 vaccination induces mucosal antibody responses in previously infected individuals. Nat. Commun. 13, 5135 (2022).
Google Scholar
Fonseca, M. H. G. et al. Persistently positive SARS-CoV-2-specific IgM during 1-year follow-up. J. Med. Virol. 94, 4037–4039 (2022).
Google Scholar
Ruggiero, A. et al. SARS-CoV-2 vaccination elicits unconventional IgM specific responses in naive and previously COVID-19-infected individuals. EBioMedicine 77, 103888 (2022).
Google Scholar
Wang, P. et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature 593, 130–135 (2021).
Google Scholar
Wang, Q. et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature 608, 603–608 (2022).
Google Scholar
Garcia-Beltran, W. F. et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell 184, 2372–2383.e2379 (2021).
Google Scholar
Hoffmann, M. et al. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell 184, 2384–2393.e2312 (2021).
Google Scholar
Planas, D. et al. Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies. Nat. Med. 27, 917–924 (2021).
Google Scholar
Havervall, S. et al. Anti-spike mucosal IgA protection against SARS-CoV-2 Omicron infection. N. Engl. J. Med. 387, 1333–1336 (2022).
Google Scholar
Ku, Z. et al. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature 595, 718–723 (2021).
Google Scholar
Hale, M. et al. IgM antibodies derived from memory B cells are potent cross-variant neutralizers of SARS-CoV-2. J. Exp. Med. 219, e20220849 (2022).
Google Scholar
Zhang, Q. et al. Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2. Nat. Commun. 12, 4210 (2021).
Google Scholar
He, P. et al. SARS-CoV-2 Delta and Omicron variants evade population antibody response by mutations in a single spike epitope. Nat. Microbiol. 7, 1635–1649 (2022).
Google Scholar
Ju, B. et al. Infection with wild-type SARS-CoV-2 elicits broadly neutralizing and protective antibodies against omicron subvariants. Nat. Immunol. 24, 690–699 (2023).
Rapp, M. et al. Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class. Cell Rep. 35, 108950 (2021).
Google Scholar
Chen, Y. et al. Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses. Nat. Rev. Immunol. 23, 189–199 (2023).
Google Scholar
Liu, L. et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456 (2020).
Google Scholar
Zhou, P. et al. Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease. Immunity 56, 669–686.e667 (2023).
Google Scholar
Makdasi, E. et al. The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against viral variants. Cell Rep. 36, 109679 (2021).
Google Scholar
Randall, T. D. Bronchus-associated lymphoid tissue (BALT). Struct. Funct. Adv. Immunol. 107, 187–241 (2010).
Google Scholar
Fleige, H. et al. IL-17-induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs. J. Exp. Med. 211, 643–651 (2014).
Google Scholar
GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).
Google Scholar
Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).
Google Scholar
Vinuesa, C. G., Linterman, M. A., Goodnow, C. C. & Randall, K. L. T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol. Rev. 237, 72–89 (2010).
Google Scholar
Vinuesa, C. G., Linterman, M. A., Yu, D. & MacLennan, I. C. Follicular Helper T Cells. Annu Rev. Immunol. 34, 335–368, (2016).
Google Scholar
Eisenbarth, S. C. et al. CD4(+) T cells that help B cells – a proposal for uniform nomenclature. Trends Immunol. 42, 658–669 (2021).
Google Scholar
Naderi, W., Schreiner, D. & King, C. G. T-cell-B-cell collaboration in the lung. Curr. Opin. Immunol. 81, 102284 (2023).
Google Scholar
Ruddle, N. H. High endothelial venules and lymphatic vessels in tertiary lymphoid organs: characteristics, functions, and regulation. Front. Immunol. 7, 491 (2016).
Google Scholar
Ruddle, N. H. Lymphatic vessels and tertiary lymphoid organs. J. Clin. Investig. 124, 953–959 (2014).
Google Scholar
Jeucken, K. C. M., Koning, J. J., Mebius, R. E. & Tas, S. W. The role of endothelial cells and TNF-receptor superfamily members in lymphoid organogenesis and function during health and inflammation. Front. Immunol. 10, 2700 (2019).
Google Scholar
Swann, O. V. et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ 370, m3249 (2020).
Google Scholar
Matsumoto, R. et al. Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity. Nat. Immunol. 24, 1370–1381 (2023).
Google Scholar
Gago da Graca, C., van Baarsen, L. G. M. & Mebius, R. E. Tertiary lymphoid structures: diversity in their development, composition, and role. J. Immunol. 206, 273–281 (2021).
Google Scholar
Krishnamurty, A. T. & Turley, S. J. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 21, 369–380 (2020).
Google Scholar
Rodda, L. B. et al. Single-Cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity 48, 1014–1028.e1016 (2018).
Google Scholar
Asam, S., Nayar, S., Gardner, D. & Barone, F. Stromal cells in tertiary lymphoid structures: architects of autoimmunity. Immunol. Rev. 302, 184–195 (2021).
Google Scholar
Khanal, S., Wieland, A. & Gunderson, A. J. Mechanisms of tertiary lymphoid structure formation: cooperation between inflammation and antigenicity. Front. Immunol. 14, 1267654 (2023).
Google Scholar
Stranford, S. & Ruddle, N. H. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: parallels with lymph node stroma. Front. Immunol. 3, 350 (2012).
Google Scholar
Barone, F. et al. Stromal fibroblasts in tertiary lymphoid structures: a novel target in chronic inflammation. Front. Immunol. 7, 477 (2016).
Google Scholar
Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).
Google Scholar
Wiley, J. A. et al. Inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. PLoS ONE 4, e7142 (2009).
Google Scholar
Moyron-Quiroz, J. E. et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25, 643–654 (2006).
Google Scholar
Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).
Google Scholar
Behr, F. M. et al. Tissue-resident memory CD8(+) T cells shape local and systemic secondary T cell responses. Nat. Immunol. 21, 1070–1081 (2020).
Google Scholar
Bosnjak, B. et al. Intranasal delivery of MVA vector vaccine induces effective pulmonary immunity against SARS-CoV-2 in Rodents. Front. Immunol. 12, 772240 (2021).
Google Scholar
Do, K. T. H. et al. The effect of Toll-like receptor agonists on the immunogenicity of MVA-SARS-2-S vaccine after intranasal administration in mice. Front. Cell Infect. Microbiol. 13, 1259822 (2023).
Google Scholar
Stewart, E. L. et al. Mucosal immunization with a delta-inulin adjuvanted recombinant spike vaccine elicits lung-resident immune memory and protects mice against SARS-CoV-2. Mucosal Immunol. 15, 1405–1415 (2022).
Google Scholar
Hindson, J. COVID-19: faecal-oral transmission? Nat. Rev. Gastroenterol. Hepatol. 17, 259 (2020).
Google Scholar
Pabst, O., Wahl, B., Bernhardt, G. & Hammerschmidt, S. I. Mesenteric lymph node stroma cells in the generation of intestinal immune responses. J. Mol. Med. 87, 945–951, (2009).
Google Scholar
Lycke, N. Y. & Bemark, M. The role of Peyer’s patches in synchronizing gut IgA responses. Front. Immunol. 3, 329 (2012).
Google Scholar
Jung, C., Hugot, J. P. & Barreau, F. Peyer’s patches: the immune sensors of the intestine. Int. J. Inflam. 2010, 823710 (2010).
Google Scholar
Kerneis, S., Bogdanova, A., Kraehenbuhl, J. P. & Pringault, E. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 277, 949–952, (1997).
Google Scholar
Fotopoulos, G. et al. Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc. Natl Acad. Sci. USA 99, 9410–9414 (2002).
Google Scholar
Jang, M. H. et al. Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 101, 6110–6115 (2004).
Google Scholar
Amerongen, H. M. et al. Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS. J. Acquir Immune Defic. Syndr. 4, 760–765 (1991).
Google Scholar
Mabbott, N. A. et al. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677 (2013).
Google Scholar
Miller, H. et al. Intestinal M cells: the fallible sentinels? World J. Gastroenterol. 13, 1477–1486 (2007).
Google Scholar
Horvath, D. et al. Novel intranasal vaccine targeting SARS-CoV-2 receptor binding domain to mucosal microfold cells and adjuvanted with TLR3 agonist Riboxxim elicits strong antibody and T-cell responses in mice. Sci. Rep. 13, 4648 (2023).
Google Scholar
Balan, S., Saxena, M. & Bhardwaj, N. Dendritic cell subsets and locations. Int. Rev. Cell Mol. Biol. 348, 1–68 (2019).
Google Scholar
Schuler, G. et al. Murine epidermal Langerhans cells as a model to study tissue dendritic cells. Adv. Exp. Med. Biol. 329, 243–249 (1993).
Google Scholar
Spits, H. et al. Innate lymphoid cells-a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Google Scholar
Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).
Google Scholar
Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).
Google Scholar
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Google Scholar
Budden, K. F. et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat. Rev. Microbiol. 15, 55–63 (2017).
Google Scholar
Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).
Google Scholar
Kim, H. Y. et al. Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J. Allergy Clin. Immunol. 129, e211–e216 (2012).
Swiecki, M. & Colonna, M. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol. Rev. 234, 142–162, (2010).
Google Scholar
Trouillet-Assant, S. et al. Type I IFN immunoprofiling in COVID-19 patients. J. Allergy Clin. Immunol. 146, 206–208.e202 (2020).
Google Scholar
Zhou, R. et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity 53, 864–877.e865 (2020).
Google Scholar
Winheim, E. et al. Impaired function and delayed regeneration of dendritic cells in COVID-19. PLoS Pathog. 17, e1009742 (2021).
Google Scholar
Perez-Gomez, A. et al. Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection. Cell Mol. Immunol. 18, 2128–2139 (2021).
Google Scholar
Sanchez-Cerrillo, I. et al. COVID-19 severity associates with pulmonary redistribution of CD1c+ DCs and inflammatory transitional and nonclassical monocytes. J. Clin. Investig. 130, 6290–6300 (2020).
Google Scholar
Merad, M., Ginhoux, F. & Collin, M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat. Rev. Immunol. 8, 935–947, (2008).
Google Scholar
Ginhoux, F. et al. Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7, 265–273 (2006).
Google Scholar
Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252, (1998).
Google Scholar
Bermejo-Jambrina, M. et al. Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans. EMBO J. 40, e106765 (2021).
Google Scholar
Ndeupen, S. et al. Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses. PLoS Pathog. 18, e1010255 (2022).
Google Scholar
Snider, C. J. et al. Poliovirus type 1 systemic humoral and intestinal mucosal immunity induced by monovalent oral poliovirus vaccine, fractional inactivated poliovirus vaccine, and bivalent oral poliovirus vaccine: A randomized controlled trial. Vaccine 41, 6083–6092 (2023).
Google Scholar
Chaturvedi, R. et al. Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage. Gastroenterology 146, 1739–1751.e1714 (2014).
Google Scholar
Zaidi, S. F. et al. Helicobacter pylori Induces Serine Phosphorylation of EGFR via Novel TAK1-p38 Activation Pathway in an HB-EGF-Independent Manner. Helicobacter 20, 381–389 (2015).
Google Scholar
Raju, D. et al. Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology 142, 1160–1171 (2012).
Google Scholar
Tahara, T. et al. Telomere length in the gastric mucosa after Helicobacter pylori eradication and its potential role in the gastric carcinogenesis. Clin. Exp. Med. 18, 21–26 (2018).
Google Scholar
Pero, R. et al. Beta-defensins and analogs in Helicobacter pylori infections: mRNA expression levels, DNA methylation, and antibacterial activity. PLoS ONE 14, e0222295 (2019).
Google Scholar
Grubman, A. et al. The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell Microbiol. 12, 626–639 (2010).
Google Scholar
Mayr, L. M., Su, B. & Moog, C. Non-neutralizing antibodies directed against HIV and their functions. Front. Immunol. 8, 1590 (2017).
Google Scholar
Ilinykh, P. A. et al. Non-neutralizing antibodies from a marburg infection survivor mediate protection by Fc-Effector Functions and by enhancing efficacy of other antibodies. Cell Host Microbe 27, 976–991.e911 (2020).
Google Scholar
Krammer, F. The human antibody response to influenza A virus infection and vaccination. Nat. Rev. Immunol. 19, 383–397 (2019).
Google Scholar
Excler, J. L. et al. Nonneutralizing functional antibodies: a new “old” paradigm for HIV vaccines. Clin. Vaccin. Immunol. 21, 1023–1036 (2014).
Google Scholar
Abreu-Mota, T. et al. Non-neutralizing antibodies elicited by recombinant Lassa-Rabies vaccine are critical for protection against Lassa fever. Nat. Commun. 9, 4223 (2018).
Google Scholar
Pedreno-Lopez, N. et al. Non-neutralizing antibodies may contribute to suppression of SIVmac239 Viremia in Indian Rhesus Macaques. Front. Immunol. 12, 657424 (2021).
Google Scholar
Forthal, D. N. & Finzi, A. Antibody-dependent cellular cytotoxicity in HIV infection. AIDS 32, 2439–2451 (2018).
Google Scholar
Katzelnick, L. C. et al. Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017).
Google Scholar
Lu, L. L., Suscovich, T. J., Fortune, S. M. & Alter, G. Beyond binding: antibody effector functions in infectious diseases. Nat. Rev. Immunol. 18, 46–61 (2018).
Google Scholar
Lee, W. S. et al. Decay of Fc-dependent antibody functions after mild to moderate COVID-19. Cell Rep. Med. 2, 100296 (2021).
Google Scholar
Grudzien, M. & Rapak, A. Effect of natural compounds on NK cell activation. J. Immunol. Res. 2018, 4868417 (2018).
Google Scholar
Vanderven, H. A., Jegaskanda, S., Wheatley, A. K. & Kent, S. J. Antibody-dependent cellular cytotoxicity and influenza virus. Curr. Opin. Virol. 22, 89–96 (2017).
Google Scholar
Hagemann, K. et al. Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients. Eur. J. Immunol. 52, 1297–1307 (2022).
Google Scholar
Yu, Y. et al. Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients. Signal. Transduct. Target Ther. 6, 346 (2021).
Google Scholar
Tauzin, A. et al. A single dose of the SARS-CoV-2 vaccine BNT162b2 elicits Fc-mediated antibody effector functions and T cell responses. Cell Host Microbe 29, 1137–1150.e1136 (2021).
Google Scholar
Garcia-Garcia, E. & Rosales, C. Signal transduction during Fc receptor-mediated phagocytosis. J. Leukoc. Biol. 72, 1092–1108, (2002).
Google Scholar
Freeman, S. A. & Grinstein, S. Phagocytosis: receptors, signal integration, and the cytoskeleton. Immunol. Rev. 262, 193–215 (2014).
Google Scholar
Herr, A. B., Ballister, E. R. & Bjorkman, P. J. Insights into IgA-mediated immune responses from the crystal structures of human FcalphaRI and its complex with IgA1-Fc. Nature 423, 614–620, (2003).
Google Scholar
Herr, A. B. et al. Bivalent binding of IgA1 to FcalphaRI suggests a mechanism for cytokine activation of IgA phagocytosis. J. Mol. Biol. 327, 645–657 (2003).
Google Scholar
Junqueira, C. et al. Fc gamma R-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature 606, 576 (2022). -+.
Google Scholar
Maemura, T. et al. Antibody-dependent enhancement of SARS-CoV-2 infection is mediated by the IgG receptors FcgammaRIIA and FcgammaRIIIA but does not contribute to aberrant cytokine production by macrophages. mBio 12, e0198721 (2021).
Google Scholar
Shimizu, J. et al. The potential of COVID-19 patients’ sera to cause antibody-dependent enhancement of infection and IL-6 production. Sci. Rep. 11, 23713 (2021).
Google Scholar
Atri, C., Guerfali, F. Z. & Laouini, D. Role of human macrophage polarization in inflammation during infectious diseases. Int. J. Mol. Sci. 19, 1801 (2018).
Kolomaznik, M., Nova, Z. & Calkovska, A. Pulmonary surfactant and bacterial lipopolysaccharide: the interaction and its functional consequences. Physiol. Res. 66, S147–S157 (2017).
Google Scholar
Shimizu, J. et al. Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells. Sci. Rep. 12, 15612 (2022).
Google Scholar
Chakraborty, S. et al. Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Sci. Transl. Med. 14, eabm7853 (2022).
Google Scholar
Zhou, W. et al. Characterization of antibody-C1q interactions by Biolayer Interferometry. Anal. Biochem. 549, 143–148 (2018).
Google Scholar
Gadjeva, M. G. et al. Interaction of human C1q with IgG and IgM: revisited. Biochemistry 47, 13093–13102 (2008).
Google Scholar
Severe Covid, G. G. et al. Genomewide association study of severe Covid-19 with respiratory failure. N. Engl. J. Med. 383, 1522–1534 (2020).
Google Scholar
Zhao, J. et al. Relationship between the ABO blood group and the Coronavirus Disease 2019 (COVID-19) susceptibility. Clin. Infect. Dis. 73, 328–331 (2021).
Google Scholar
Deschasaux-Tanguy, M. et al. ABO blood types and SARS-CoV-2 infection assessed using seroprevalence data in a large population-based sample: the SAPRIS-SERO multi-cohort study. Sci. Rep. 13, 4775 (2023).
Google Scholar
Deleers, M. et al. Covid-19 and blood groups: ABO antibody levels may also matter. Int. J. Infect. Dis. 104, 242–249 (2021).
Google Scholar
Beaudoin-Bussieres, G. et al. A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection. Cell Rep. 38, 110368 (2022).
Google Scholar
Carragher, D. M. et al. A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. J. Immunol. 181, 4168–4176 (2008).
Google Scholar
Burton, D. R. Antibodies, viruses and vaccines. Nat. Rev. Immunol. 2, 706–713 (2002).
Google Scholar
Weidenbacher, P. A. et al. Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors. Nat. Chem. Biol. 18, 1270–1276 (2022).
Google Scholar
Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).
Google Scholar
Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665, (2004).
Google Scholar
Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).
Google Scholar
Bunker, J. J. et al. Innate and adaptive humoral responses coat distinct commensal bacteria with Immunoglobulin A. Immunity 43, 541–553 (2015).
Google Scholar
Bunker, J. J. et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science 358, eaan6619 (2017).
Google Scholar
Mathias, A. et al. Potentiation of polarized intestinal Caco-2 cell responsiveness to probiotics complexed with secretory IgA. J. Biol. Chem. 285, 33906–33913 (2010).
Google Scholar
Bollinger, R. R. et al. Human secretory immunoglobulin A may contribute to biofilm formation in the gut. Immunology 109, 580–587 (2003).
Google Scholar
McLoughlin, K. et al. Host selection of microbiota via differential adhesion. Cell Host Microbe 19, 550–559 (2016).
Google Scholar
Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl. Med. 7, 316ra192 (2015).
Google Scholar
Mouquet, H. et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467, 591–595 (2010).
Google Scholar
Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633–1637 (2011).
Google Scholar
Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906–1908 (2005).
Google Scholar
Zang, R. et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci. Immunol. 5, eabc3582 (2020).
Conlon, M. A. & Bird, A. R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 17–44 (2014).
Google Scholar
Martin, R. et al. Role of commensal and probiotic bacteria in human health: a focus on inflammatory bowel disease. Micro. Cell Fact. 12, 71 (2013).
Google Scholar
Pickard, J. M., Zeng, M. Y., Caruso, R. & Nunez, G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol. Rev. 279, 70–89 (2017).
Google Scholar
Ding, J. H. et al. Role of gut microbiota via the gut-liver-brain axis in digestive diseases. World J. Gastroenterol. 26, 6141–6162 (2020).
Google Scholar
Shenoy, S. Gut microbiome, Vitamin D, ACE2 interactions are critical factors in immune-senescence and inflammaging: key for vaccine response and severity of COVID-19 infection. Inflamm. Res. 71, 13–26 (2022).
Google Scholar
Zuo, T. et al. Alterations in gut microbiota of patients With COVID-19 during time of hospitalization. Gastroenterology 159, 944–955 e948 (2020).
Google Scholar
Xia, Q. et al. Investigating efficacy of “microbiota modulation of the gut-lung Axis” combined with chemotherapy in patients with advanced NSCLC: study protocol for a multicenter, prospective, double blind, placebo controlled, randomized trial. BMC Cancer 21, 721 (2021).
Google Scholar
Mullish, B. H. et al. Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: should we be considering probiotics during viral pandemics? Gut Microbes 13, 1–9 (2021).
Google Scholar
Panebianco, C. et al. Probiotic Bifidobacterium lactis, anti-oxidant vitamin E/C and anti-inflammatory dha attenuate lung inflammation due to pm2.5 exposure in mice. Benef. Microbes 10, 69–75, (2019).
Google Scholar
Gutierrez-Castrellon, P. et al. Probiotic improves symptomatic and viral clearance in Covid19 outpatients: a randomized, quadruple-blinded, placebo-controlled trial. Gut Microbes 14, 2018899 (2022).
Google Scholar
Zuo, T. et al. Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge. Gastroenterology 159, 1302–1310.e1305 (2020).
Google Scholar
Liu, Q. et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut 71, 544–552 (2022).
Google Scholar
Troseid, M. et al. Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19. Crit. Care 27, 69 (2023).
Google Scholar
Gu, S. et al. Alterations of the gut microbiota in patients with Coronavirus Disease 2019 or H1N1 influenza. Clin. Infect. Dis. 71, 2669–2678 (2020).
Google Scholar
Zuo, T. et al. Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity. Microbiome 9, 91 (2021).
Google Scholar
Cao, J. et al. Integrated gut virome and bacteriome dynamics in COVID-19 patients. Gut Microbes 13, 1–21 (2021).
Google Scholar
Zhang, F. et al. Gut microbiota in COVID-19: key microbial changes, potential mechanisms and clinical applications. Nat. Rev. Gastroenterol. Hepatol 20, 323–337 (2023).
Google Scholar
Yeoh, Y. K. et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut 70, 698–706 (2021).
Google Scholar
Wang, B. et al. Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions. Signal. Transduct. Target Ther. 7, 143 (2022).
Google Scholar
Zhou, Y. et al. Gut microbiota dysbiosis correlates with abnormal immune response in moderate COVID-19 patients with fever. J. Inflamm. Res. 14, 2619–2631 (2021).
Google Scholar
Chakraborty, C. et al. Altered gut microbiota patterns in COVID-19: Markers for inflammation and disease severity. World J. Gastroenterol. 28, 2802–2822 (2022).
Google Scholar
Viana, S. D., Nunes, S. & Reis, F. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis. Ageing Res. Rev. 62, 101123 (2020).
Google Scholar
Kuster, G. M. et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur. Heart J. 41, 1801–1803 (2020).
Google Scholar
Bernard-Raichon, L. et al. Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia. Nat. Commun. 13, 5926 (2022).
Google Scholar
Dang, A. T. & Marsland, B. J. Microbes, metabolites, and the gut-lung axis. Mucosal Immunol. 12, 843–850 (2019).
Google Scholar
Sui, H. et al. Effective treatment of a child with adenoidal hypertrophy and severe asthma by omalizumab: a case report. Allergy Asthma Clin. Immunol. 18, 94 (2022).
Google Scholar
Ungkanont, K. et al. Association between adenoid bacteriology and clinical characteristics of adenoid-related diseases in children. SAGE Open Med. 9, 20503121211006005 (2021).
Google Scholar
Yu, H. et al. Diagnosis and treatment of herpangina: Chinese expert consensus. World J. Pediatr. 16, 129–134 (2020).
Google Scholar
Le, T. V., Mironova, E., Garcin, D. & Compans, R. W. Induction of influenza-specific mucosal immunity by an attenuated recombinant Sendai virus. PLoS ONE 6, e18780 (2011).
Google Scholar
Wang, T. et al. Influenza-trained mucosal-resident alveolar macrophages confer long-term antitumor immunity in the lungs. Nat. Immunol. 24, 423–438 (2023).
Google Scholar
Habibi, M. S. et al. Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection. Science. 370, eaba9301 (2020).
Philips, J. A. & Ernst, J. D. Tuberculosis pathogenesis and immunity. Annu. Rev. Pathol. 7, 353–384, (2012).
Google Scholar
Zhou, S. & Aitken, S. L. Prophylaxis Against Pneumocystis jirovecii Pneumonia in Adults. JAMA 330, 182–183 (2023).
Google Scholar
Gans, M. D. & Gavrilova, T. Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes. Paediatr. Respir. Rev. 36, 118–127 (2020).
Google Scholar
Hansel, T. T., Johnston, S. L. & Openshaw, P. J. Microbes and mucosal immune responses in asthma. Lancet 381, 861–873, (2013).
Google Scholar
Parker, D. & Prince, A. Immunopathogenesis of Staphylococcus aureus pulmonary infection. Semin Immunopathol. 34, 281–297, (2012).
Google Scholar
Lan, F. et al. Staphylococcus aureus Induces a Mucosal Type 2 Immune Response via Epithelial Cell-derived Cytokines. Am. J. Respir. Crit. Care Med. 198, 452–463 (2018).
Google Scholar
Caruso, R., Lo, B. C. & Nunez, G. Host-microbiota interactions in inflammatory bowel disease. Nat. Rev. Immunol. 20, 411–426 (2020).
Google Scholar
Targan, S. R. & Karp, L. C. Defects in mucosal immunity leading to ulcerative colitis. Immunol. Rev. 206, 296–305 (2005).
Google Scholar
Moyat, M. & Velin, D. Immune responses to Helicobacter pylori infection. World J. Gastroenterol. 20, 5583–5593, (2014).
Google Scholar
Catassi, C., Verdu, E. F., Bai, J. C. & Lionetti, E. Coeliac disease. Lancet 399, 2413–2426 (2022).
Google Scholar
Blutt, S. E. et al. IgA is important for clearance and critical for protection from rotavirus infection. Mucosal Immunol. 5, 712–719 (2012).
Google Scholar
Yahiaoui, R. Y. et al. Prevalence and antibiotic resistance of commensal Streptococcus pneumoniae in nine European countries. Future Microbiol. 11, 737–744 (2016).
Google Scholar
Abdullahi, O. et al. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PLoS ONE 7, e30787 (2012).
Google Scholar
Bogaert, D., De Groot, R. & Hermans, P. W. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154, (2004).
Google Scholar
Davis, K. M., Akinbi, H. T., Standish, A. J. & Weiser, J. N. Resistance to mucosal lysozyme compensates for the fitness deficit of peptidoglycan modifications by Streptococcus pneumoniae. PLoS Pathog. 4, e1000241 (2008).
Google Scholar
Chan, J. M. et al. Bacterial surface lipoproteins mediate epithelial microinvasion by Streptococcus pneumoniae. Infect. Immun. 92, e0044723 (2024).
Google Scholar
Caputo, V. et al. The initial interplay between HIV and mucosal innate immunity. Front. Immunol. 14, 1104423 (2023).
Google Scholar
Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 204 (2007).
Google Scholar
Liu, J. Z. et al. Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe 11, 227–239 (2012).
Google Scholar
Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).
Google Scholar
Winter, S. E. et al. Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467, 426–429 (2010).
Google Scholar
Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).
Google Scholar
MacLennan, C. A. et al. The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children. J. Clin. Investig 118, 1553–1562 (2008).
Google Scholar
Ma, J., Rubin, B. K. & Voynow, J. A. Mucins, Mucus, and Goblet Cells. Chest 154, 169–176 (2018).
Google Scholar
McAuley, J. L. et al. The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunol. 10, 1581–1593 (2017).
Google Scholar
Shui, J. W. et al. HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria. Nature 488, 222–225 (2012).
Google Scholar
De Cock, K. M., Brun-Vezinet, F. & Soro, B. HIV-1 and HIV-2 infections and AIDS in West Africa. AIDS 5, S21–S28 (1991).
Google Scholar
Gustine, J. N. & Jones, D. Immunopathology of Hyperinflammation in COVID-19. Am. J. Pathol. 191, 4–17 (2021).
Google Scholar
Akira, S. & Hemmi, H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett. 85, 85–95 (2003).
Google Scholar
Khan, S. et al. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. Elife. 10, e68563 (2021).
Qian, Y. et al. Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin. J. Virol. 95, e0139621 (2021).
Google Scholar
Zheng, M. et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat. Immunol. 22, 829–838 (2021).
Google Scholar
Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).
Google Scholar
Zhao, Y. et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res 31, 818–820 (2021).
Google Scholar
Shirato, K. & Kizaki, T. SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages. Heliyon 7, e06187 (2021).
Google Scholar
Moreno-Eutimio, M. A., Lopez-Macias, C. & Pastelin-Palacios, R. Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. Microbes Infect. 22, 226–229 (2020).
Google Scholar
Salvi, V. et al. SARS-CoV-2-associated ssRNAs activate inflammation and immunity via TLR7/8. JCI Insight 6, e150542 (2021).
Google Scholar
Bortolotti, D. et al. TLR3 and TLR7 RNA Sensor Activation during SARS-CoV-2 Infection. Microorganisms 9, 1820 (2021).
Google Scholar
Wallach, T. et al. Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia. Front. Immunol. 13, 1066456 (2022).
Google Scholar
Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).
Google Scholar
Han, L. et al. SARS-CoV-2 ORF9b antagonizes type I and III interferons by targeting multiple components of the RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING signaling pathways. J. Med. Virol. 93, 5376–5389 (2021).
Google Scholar
Deng, J. et al. SARS-CoV-2 NSP7 inhibits type I and III IFN production by targeting the RIG-I/MDA5, TRIF, and STING signaling pathways. J. Med. Virol. 95, e28561 (2023).
Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).
Google Scholar
Costa, T. J. et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vasc. Pharm. 142, 106946 (2022).
Google Scholar
Bezemer, G. F. G. & Garssen, J. TLR9 and COVID-19: a multidisciplinary theory of a multifaceted therapeutic target. Front. Pharm. 11, 601685 (2020).
Google Scholar
Ou, B. S. et al. Nanoparticle-Conjugated Toll-Like Receptor 9 Agonists Improve the Potency, Durability, and Breadth of COVID-19 Vaccines. ACS Nano 18, 3214–3233 (2024).
Google Scholar
Roh, J. S. & Sohn, D. H. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 18, e27 (2018).
Google Scholar
Parthasarathy, U. et al. The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders. Biochem. Pharm. 195, 114847 (2022).
Google Scholar
Liu, T., Zhang, L., Joo, D. & Sun, S. C. NF-kappaB signaling in inflammation. Signal. Transduct. Target Ther. 2, 17023 (2017).
Google Scholar
Kawai, T. & Akira, S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol. Med. 13, 460–469, (2007).
Google Scholar
Li, W. et al. SARS-CoV-2 Nsp5 Activates NF-kappaB Pathway by Upregulating SUMOylation of MAVS. Front. Immunol. 12, 750969 (2021).
Google Scholar
Nie, Y. et al. SARS-CoV-2 ORF3a positively regulates NF-kappaB activity by enhancing IKKbeta-NEMO interaction. Virus Res. 328, 199086 (2023).
Google Scholar
Guo, Y. et al. Targeting TNF-alpha for COVID-19: recent advanced and controversies. Front. Public Health 10, 833967 (2022).
Google Scholar
Cokic, V. P. et al. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms. Mediators Inflamm. 2015, 453020 (2015).
Google Scholar
Satarker, S. et al. JAK-STAT pathway inhibition and their implications in COVID-19 Therapy. Postgrad. Med. 133, 489–507 (2021).
Google Scholar
Domizio, J. D. et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature 603, 145–151 (2022).
Google Scholar
Su, J. et al. SARS-CoV-2 ORF3a inhibits cGAS-STING-mediated autophagy flux and antiviral function. J. Med. Virol. 95, e28175 (2023).
Google Scholar
Han, L. et al. SARS-CoV-2 ORF10 antagonizes STING-dependent interferon activation and autophagy. J. Med. Virol. 94, 5174–5188 (2022).
Google Scholar
Hafezi, B. et al. Cytokine Storm Syndrome in SARS-CoV-2 Infections: a functional role of mast cells. Cells. 10, 1761 (2021).
Song, P. et al. Cytokine storm induced by SARS-CoV-2. Clin. Chim. Acta 509, 280–287 (2020).
Google Scholar
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
Google Scholar
Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014).
Google Scholar
Van Limbergen, J., Radford-Smith, G. & Satsangi, J. Advances in IBD genetics. Nat. Rev. Gastroenterol. Hepatol. 11, 372–385 (2014).
Google Scholar
Jain, U. et al. Debaryomyces is enriched in Crohn’s disease intestinal tissue and impairs healing in mice. Science 371, 1154–1159 (2021).
Google Scholar
Martini, G. R. et al. Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T(H)1 cell responses in Crohn’s disease. Nat. Med. 29, 2602–2614 (2023).
Google Scholar
Lloyd-Price, J. et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569, 655–662 (2019).
Google Scholar
Blander, J. M. et al. Regulation of inflammation by microbiota interactions with the host. Nat. Immunol. 18, 851–860 (2017).
Google Scholar
Rouxel, O. et al. Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes. Nat. Immunol. 18, 1321–1331 (2017).
Google Scholar
Kumar, V. Innate Lymphoid Cells and Adaptive Immune Cells Cross-Talk: A Secret Talk Revealed in Immune Homeostasis and Different Inflammatory Conditions. Int. Rev. Immunol. 40, 217–251 (2021).
Google Scholar
Song, X. et al. Gut microbial fatty acid isomerization modulates intraepithelial T cells. Nature 619, 837–843 (2023).
Google Scholar
Conrey, P. E. et al. IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation. Sci. Immunol. 8, eade2335 (2023).
Google Scholar
Gesualdo, L., Di Leo, V. & Coppo, R. The mucosal immune system and IgA nephropathy. Semin. Immunopathol. 43, 657–668 (2021).
Google Scholar
Zaiss, M. M. et al. The gut-joint axis in rheumatoid arthritis. Nat. Rev. Rheumatol. 17, 224–237 (2021).
Google Scholar
Jubair, W. K. et al. Modulation of inflammatory arthritis in mice by gut microbiota through mucosal inflammation and autoantibody generation. Arthritis Rheumatol. 70, 1220–1233 (2018).
Google Scholar
Tajik, N. et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat. Commun. 11, 1995 (2020).
Google Scholar
Fechtner, S. et al. 3,3-dimethyl-1-butanol and its metabolite 3,3-dimethylbutyrate ameliorate collagen-induced arthritis independent of choline trimethylamine lyase activity. Inflamm. https://doi.org/10.1007/s10753-024-02126-y.
Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).
Google Scholar
Ogunrinde, E. et al. A link between plasma microbial translocation, microbiome, and autoantibody development in first-degree relatives of systemic lupus erythematosus patients. Arthritis Rheumatol. 71, 1858–1868 (2019).
Google Scholar
Thim-Uam, A. et al. Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus. Sci. Rep. 10, 777 (2020).
Google Scholar
Sorini, C. et al. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proc. Natl Acad. Sci. USA 116, 15140–15149 (2019).
Google Scholar
Joesten, W. C., Short, A. H. & Kennedy, M. A. Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice. BMJ Open Diabetes Res. Care 7, e000793 (2019).
Google Scholar
Watts, T. et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc. Natl Acad. Sci. USA 102, 2916–2921 (2005).
Google Scholar
Rouland, M. et al. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia. Gut 71, 296–308 (2022).
Google Scholar
Costa, F. R. et al. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset. J. Exp. Med. 213, 1223–1239 (2016).
Google Scholar
van Heck, J. I. P. et al. The gut microbiome composition is altered in long-standing Type 1 Diabetes and Associates With Glycemic control and disease-related complications. Diabetes Care 45, 2084–2094 (2022).
Google Scholar
Bohaumilitzky, L. et al. The different immune profiles of normal colonic mucosa in cancer-free Lynch Syndrome Carriers and Lynch syndrome colorectal cancer patients. Gastroenterology 162, 907–919.e910 (2022).
Google Scholar
Li, W. et al. All-Trans-Retinoic Acid-Adjuvanted mRNA Vaccine Induces Mucosal Anti-Tumor Immune Responses for Treating Colorectal Cancer. Adv. Sci. 11, e2309770 (2024).
Google Scholar
Polack, F. P. et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Google Scholar
Sahin, U. et al. COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses. Nature 586, 594–599 (2020).
Google Scholar
Owen, D. R. et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science 374, 1586–1593 (2021).
Google Scholar
Pillaiyar, T. et al. An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem. 59, 6595–6628 (2016).
Google Scholar
Lavelle, E. C. & Ward, R. W. Mucosal vaccines – fortifying the frontiers. Nat. Rev. Immunol. 22, 236–250 (2022).
Google Scholar
Ren, C. et al. Respiratory Mucosal Immunity: Kinetics of Secretory Immunoglobulin A in Sputum and Throat Swabs From COVID-19 Patients and Vaccine Recipients. Front. Microbiol. 13, 782421 (2022).
Google Scholar
Pietrzak, B. et al. Secretory IgA in intestinal mucosal secretions as an adaptive barrier against microbial cells. Int. J. Mol. Sci. 21, 9254 (2020).
Kwong, K. W. et al. Oral Vaccines: A Better Future of Immunization. Vaccines 11, 1232 (2023).
Mao, T. et al. Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses. Science 378, eabo2523 (2022).
Google Scholar
Ku, M. W. et al. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models. Cell Host Microbe 29, 236–249 e236 (2021).
Google Scholar
Hassan, A. O. et al. An intranasal vaccine durably protects against SARS-CoV-2 variants in mice. Cell Rep. 36, 109452 (2021).
Google Scholar
Afkhami, S. et al. Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell 185, 896–915.e819 (2022).
Google Scholar
Xu, F. et al. Safety, mucosal and systemic immunopotency of an aerosolized adenovirus-vectored vaccine against SARS-CoV-2 in rhesus macaques. Emerg. Microbes Infect. 11, 438–441 (2022).
Google Scholar
Zhong, J. et al. Heterologous booster with inhaled adenovirus vector COVID-19 vaccine generated more neutralizing antibodies against different SARS-CoV-2 variants. Emerg. Microbes Infect. 11, 2689–2697 (2022).
Google Scholar
Le Nouen, C. et al. Intranasal pediatric parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in monkeys. Cell 185, 4811–4825 e4817 (2022).
Google Scholar
Langel, S. N. et al. Adenovirus type 5 SARS-CoV-2 vaccines delivered orally or intranasally reduced disease severity and transmission in a hamster model. Sci. Transl. Med. 14, eabn6868 (2022).
Google Scholar
Suberi, A. et al. Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination. Sci. Transl. Med. 15, eabq0603 (2023).
Google Scholar
He, C. et al. Trimeric protein vaccine based on Beta variant elicits robust immune response against BA.4/5-included SARS-CoV-2 Omicron variants. Mol. Biomed. 4, 9 (2023).
Google Scholar
Wang, Z. et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. Nat. Biomed. Eng. 6, 791–805 (2022).
Google Scholar
Popowski, K. D. et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter 5, 2960–2974 (2022).
Google Scholar
Jiang, L. et al. A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants. J. Extracell. Vesicles 11, e12192 (2022).
Google Scholar
Marcotte, H. et al. Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages. Proc. Natl Acad. Sci. USA 121, e2315354120 (2024).
Google Scholar
Matsuda, K. et al. A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity. J. Clin. Investig. 131, e140794 (2021).
Google Scholar
Qin, T. et al. Mucosal vaccination for influenza protection enhanced by catalytic immune-adjuvant. Adv. Sci. 7, 2000771 (2020).
Google Scholar
McMahan, K. et al. Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques. Nature 626, 385–391 (2024).
Google Scholar
Bellier, B. et al. A Thermostable Oral SARS-CoV-2 Vaccine Induces Mucosal and Protective Immunity. Front. Immunol. 13, 837443 (2022).
Google Scholar
Ashraf, M. U. et al. COVID-19 Vaccines (Revisited) and Oral-Mucosal Vector System as a Potential Vaccine Platform. Vaccines 9, 171 (2021).
Google Scholar
Kocabiyik, O. et al. Vaccine targeting to mucosal lymphoid tissues promotes humoral immunity in the gastrointestinal tract. Sci. Adv. 10, eadn7786 (2024).
Google Scholar
Azzi, L. et al. Mucosal immune response in BNT162b2 COVID-19 vaccine recipients. EBioMedicine 75, 103788 (2022).
Google Scholar
Sheikh-Mohamed, S. et al. Systemic and mucosal IgA responses are variably induced in response to SARS-CoV-2 mRNA vaccination and are associated with protection against subsequent infection. Mucosal Immunol. 15, 799–808 (2022).
Google Scholar
Piano Mortari, E. et al. Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA. Cells. 10, 2541 (2021).
Tang, J. et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7, eadd4853 (2022).
Google Scholar
Alturaiki, W. Considerations for Novel COVID-19 Mucosal Vaccine Development. Vaccines 10, 1173 (2022).
Lambiase, A. et al. Evaluation of the effectiveness of BNT162b2 primary vaccination and booster dose to SARS-CoV-2 in eliciting stable mucosal immunity. Biomedicines 10, 2430 (2022).
Google Scholar
Azzi, L. et al. Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine. EBioMedicine 88, 104435 (2023).
Google Scholar
Kingstad-Bakke, B. et al. Vaccine-induced systemic and mucosal T cell immunity to SARS-CoV-2 viral variants. Proc. Natl Acad. Sci. USA 119, e2118312119 (2022).
Google Scholar
Baker, J. R. Jr., Farazuddin, M., Wong, P. T. & O’Konek, J. J. The unfulfilled potential of mucosal immunization. J. Allergy Clin. Immunol. 150, 1–11 (2022).
Google Scholar
Luria-Perez, R., Sanchez-Vargas, L. A., Munoz-Lopez, P. & Mellado-Sanchez, G. Mucosal vaccination: a promising alternative against flaviviruses. Front. Cell Infect. Microbiol. 12, 887729 (2022).
Google Scholar
Overton, E. T. et al. Intranasal seasonal influenza vaccine and a TLR-3 agonist, rintatolimod, induced cross-reactive IgA antibody formation against avian H5N1 and H7N9 influenza HA in humans. Vaccine 32, 5490–5495 (2014).
Google Scholar
Eiden, J. et al. Intranasal M2SR (M2-Deficient Single Replication) H3N2 influenza vaccine provides enhanced mucosal and serum antibodies in adults. J. Infect. Dis. 227, 103–112 (2022).
Google Scholar
Gurwith, M. et al. Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study. Lancet Infect. Dis. 13, 238–250 (2013).
Google Scholar
Ascough, S. et al. Local and systemic immunity against respiratory syncytial virus induced by a novel intranasal vaccine. a randomized, double-blind, placebo-controlled clinical trial. Am. J. Respir. Crit. Care Med. 200, 481–492 (2019).
Google Scholar
Blume, S. & Geesink, I. A brief history of polio vaccines. Science 288, 1593–1594, (2000).
Google Scholar
Counoupas, C. et al. Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis. NPJ Vaccines 5, 105 (2020).
Google Scholar
Ciarlet, M. & Schodel, F. Development of a rotavirus vaccine: clinical safety, immunogenicity, and efficacy of the pentavalent rotavirus vaccine, RotaTeq. Vaccine 27, G72–G81 (2009).
Google Scholar
Pezzoli, L., Oral Cholera Vaccine Working Group of the Global Task Force on Cholera, C. Global oral cholera vaccine use, 2013-2018. Vaccine 38, A132–A140 (2020).
Google Scholar
Wang, D. et al. Liposomal oral DNA vaccine (mycobacterium DNA) elicits immune response. Vaccine 28, 3134–3142 (2010).
Google Scholar
Ramanathan, R. & Woodrow, K. Engineering immunity in the mucosal niche against sexually transmitted infections. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 8, 107–122, (2016).
Google Scholar
Bernasconi, V. et al. A vaccine combination of lipid nanoparticles and a cholera toxin adjuvant derivative greatly improves lung protection against influenza virus infection. Mucosal Immunol. 14, 523–536 (2021).
Google Scholar
Hartwell, B. L. et al. Intranasal vaccination with lipid-conjugated immunogens promotes antigen transmucosal uptake to drive mucosal and systemic immunity. Sci. Transl. Med. 14, eabn1413 (2022).
Google Scholar
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).
Google Scholar
Camacho, A. I. et al. Nanoparticle-based vaccine for mucosal protection against Shigella flexneri in mice. Vaccine 31, 3288–3294 (2013).
Google Scholar
Sawaengsak, C. et al. Chitosan nanoparticle encapsulated hemagglutinin-split influenza virus mucosal vaccine. AAPS PharmSciTech 15, 317–325 (2014).
Google Scholar
Knight, F. C. et al. Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8(+) Lung-Resident Memory T Cells. ACS Nano 13, 10939–10960 (2019).
Google Scholar
Zhu, Q. et al. Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat. Med. 18, 1291–1296 (2012).
Google Scholar
Sanchez-Guzman, D. et al. Silver nanoparticle-adjuvanted vaccine protects against lethal influenza infection through inducing BALT and IgA-mediated mucosal immunity. Biomaterials 217, 119308 (2019).
Google Scholar
Joyce, M. G. et al. A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates. Sci. Transl. Med. 14, eabi5735 (2022).
Google Scholar
Zhang, X. et al. A mosaic nanoparticle vaccine elicits potent mucosal immune response with significant cross-protection activity against multiple SARS-CoV-2 sublineages. Adv. Sci. 10, e2301034 (2023).
Google Scholar
Zhong, X. et al. Nanovaccines mediated subcutis-to-intestine cascade for improved protection against intestinal infections. Small 18, e2105530 (2022).
Google Scholar
Li, M. et al. Rapid induction of long-lasting systemic and mucosal immunity via thermostable microneedle-mediated chitosan oligosaccharide-encapsulated DNA Nanoparticles. ACS Nano 17, 24200–24217 (2023).
Google Scholar
Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463, (2010).
Google Scholar
Dougan, M. et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. N. Engl. J. Med. 385, 1382–1392 (2021).
Google Scholar
Hayek, S. et al. Effectiveness of REGEN-COV antibody combination in preventing severe COVID-19 outcomes. Nat. Commun. 13, 4480 (2022).
Google Scholar
Gupta, A. et al. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N. Engl. J. Med. 385, 1941–1950 (2021).
Google Scholar
Nichols, R. M., Deveau, C. & Upadhyaya, H. Bebtelovimab: considerations for global access to treatments during a rapidly evolving pandemic. Lancet Infect. Dis. 22, 1531 (2022).
Google Scholar
Yang, Z. et al. Inhalable antibodies for the treatment of COVID-19. Innovation 3, 100328 (2022).
Google Scholar
Piepenbrink, M. S. et al. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Rep. Med. 2, 100218 (2021).
Google Scholar
Minenkova, O. et al. Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy. Mol. Ther. 30, 1979–1993 (2022).
Google Scholar
Li, C. et al. Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody. Cell 185, 1389–1401.e1318 (2022).
Google Scholar
Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 186, 279–286.e278 (2023).
Google Scholar
Yue, C. et al. ACE2 binding and antibody evasion in enhanced transmissibility of XBB.1.5. Lancet Infect. Dis. 23, 278–280 (2023).
Google Scholar
Corti, D., Purcell, L. A., Snell, G. & Veesler, D. Tackling COVID-19 with neutralizing monoclonal antibodies. Cell 184, 4593–4595 (2021).
Google Scholar
Koenig, P. A. et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science. 371, eabe6230 (2021).
Huo, J. et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat. Commun. 12, 5469 (2021).
Google Scholar
Nambulli, S. et al. Inhalable Nanobody (PiN-21) prevents and treats SARS-CoV-2 infections in Syrian hamsters at ultra-low doses. Sci. Adv. 7, eabh0319 (2021).
Guo, D. et al. Omicron-included mutation-induced changes in epitopes of SARS-CoV-2 spike protein and effectiveness assessments of current antibodies. Mol. Biomed. 3, 12 (2022).
Google Scholar
Brevini, T. et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature 615, 134–142 (2023).
Google Scholar
Devalaraja-Narashimha, K. et al. Association of complement pathways with COVID-19 severity and outcomes. Microbes Infect. 25, 105081 (2023).
Google Scholar
Kimmig, L. M. et al. IL-6 Inhibition in Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections. Front. Med. 7, 583897 (2020).
Google Scholar
Walz, L. et al. JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. BMC Infect. Dis. 21, 47 (2021).
Google Scholar
Han, Y. et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589, 270–275 (2021).
Google Scholar
Ramezankhani, R. et al. Organoid and microfluidics-based platforms for drug screening in COVID-19. Drug Discov. Today 27, 1062–1076 (2022).
Google Scholar
Tamtaji, O. R. et al. Clinical and metabolic response to probiotic administration in people with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. Clin. Nutr. 38, 1031–1035 (2019).
Google Scholar
Gopalakrishnan, V. et al. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33, 570–580 (2018).
Google Scholar
Chen, L. et al. The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: An open-label, randomized clinical trial. EBioMedicine 35, 87–96 (2018).
Google Scholar
Yu, Z. et al. The gut microbiome: a line of defense against tuberculosis development. Front. Cell Infect. Microbiol. 13, 1149679 (2023).
Google Scholar
Johnstone, J. et al. Effect of probiotics on incident ventilator-associated pneumonia in critically Ill patients: a randomized clinical trial. JAMA 326, 1024–1033 (2021).
Google Scholar
Jian, Y. et al. The impact of gut microbiota on radiation-induced enteritis. Front. Cell Infect. Microbiol. 11, 586392 (2021).
Google Scholar
Yan, X. et al. Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis. Cell Mol. Immunol. 18, 2344–2357 (2021).
Google Scholar
Rodriguez, J. A. M. et al. Effect and Tolerability of a Nutritional Supplement Based on a Synergistic Combination of beta-Glucans and Selenium- and Zinc-Enriched Saccharomyces cerevisiae (ABB C1((R))) in Volunteers Receiving the Influenza or the COVID-19 Vaccine: a Randomized, Double-Blind, Placebo-Controlled Study. Nutrients. 13, 4347 (2021).
De Boeck, I. et al. Randomized, Double-Blind, Placebo-Controlled Trial of a Throat Spray with Selected Lactobacilli in COVID-19 Outpatients. Microbiol. Spectr. 10, e0168222 (2022).
Google Scholar
Siracusa, F. et al. Short-term dietary changes can result in mucosal and systemic immune depression. Nat. Immunol. 24, 1473–1486 (2023).
Google Scholar
Sparks, R. et al. Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19. Nature 614, 752–761 (2023).
Google Scholar
Mansell, V., Hall Dykgraaf, S., Kidd, M. & Goodyear-Smith, F. Long COVID and older people. Lancet Healthy Longev. 3, e849–e854 (2022).
Google Scholar
Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol 21, 133–146 (2023).
Google Scholar
Xu, E., Xie, Y. & Al-Aly, Z. Long-term neurologic outcomes of COVID-19. Nat. Med. 28, 2406–2415 (2022).
Google Scholar
Bowe, B., Xie, Y. & Al-Aly, Z. Postacute sequelae of COVID-19 at 2 years. Nat. Med. 29, 2347–2357 (2023).
Thaweethai, T. et al. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA 329, 1934–1946 (2023).
Google Scholar
Parker, A. M. et al. Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care. Lancet Respir. Med. 9, 1328–1341 (2021).
Google Scholar
Sumi, T. & Harada, K. Immune response to SARS-CoV-2 in severe disease and long COVID-19. iScience 25, 104723 (2022).
Google Scholar
Proal, A. D. et al. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC). Nat. Immunol. 24, 1616–1627 (2023).
Zollner, A. et al. Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in Inflammatory Bowel Diseases. Gastroenterology 163, 495–506.e498 (2022).
Google Scholar
Cheong, J. G. et al. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors. Cell 186, 3882–3902.e3824 (2023).
Google Scholar
Schultheiss, C. et al. The IL-1beta, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. Cell Rep. Med. 3, 100663 (2022).
Google Scholar
Li, Z. et al. Innate immune imprints in SARS-CoV-2 Omicron variant infection convalescents. Signal. Transduct. Target Ther. 7, 377 (2022).
Google Scholar
Woodruff, M. C. et al. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat. Commun. 14, 4201 (2023).
Google Scholar
Cheon, I. S. et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci. Immunol. 6, eabk1741 (2021).
Google Scholar
Woodruff, M. C. et al. Dysregulated naive B cells and de novo autoreactivity in severe COVID-19. Nature 611, 139–147 (2022).
Google Scholar
Peluso, M. J. et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep. 36, 109518 (2021).
Google Scholar
Minutolo, A. et al. Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection. Int. Immunopharmacol. 118, 110055 (2023).
Google Scholar
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