• This record comes from PubMed

Role of IgA1 protease-producing bacteria in SARS-CoV-2 infection and transmission: a hypothesis

. 2024 Oct 16 ; 15 (10) : e0083324. [epub] 20240829

Language English Country United States Media print-electronic

Document type Journal Article

Secretory (S) IgA antibodies against severe acute respiratory syndrome (SARS)-CoV-2 are induced in saliva and upper respiratory tract (URT) secretions by natural infection and may be critical in determining the outcome of initial infection. Secretory IgA1 (SIgA1) is the predominant isotype of antibodies in these secretions. Neutralization of SARS-CoV-2 is most effectively accomplished by polymeric antibodies such as SIgA. We hypothesize that cleavage of SIgA1 antibodies against SARS-CoV-2 by unique bacterial IgA1 proteases to univalent Fabα antibody fragments with diminished virus neutralizing activity would facilitate the descent of the virus into the lungs to cause serious disease and also enhance its airborne transmission to others. Recent studies of the nasopharyngeal microbiota of patients with SARS-CoV-2 infection have revealed significant increases in the proportions of IgA1 protease-producing bacteria in comparison with healthy subjects. Similar considerations might apply also to other respiratory viral infections including influenza, possibly explaining the original attribution of influenza to Haemophilus influenzae, which produces IgA1 protease.

See more in PubMed

Russell MW, Mestecky J. 2022. Mucosal immunity: the missing link in comprehending SARS-CoV-2 infection and transmission. Front Immunol 13:957107. doi:10.3389/fimmu.2022.957107 PubMed DOI PMC

Bladh O, Aguilera K, Marking U, Kihlgren M, Greilert Norin N, Smed-Sörensen A, Sällberg Chen M, Klingström J, Blom K, Russell MW, Havervall S, Thålin C, Åberg M. 2024. Comparison of SARS-CoV-2 spike-specific IgA and IgG in nasal secretions, saliva and serum. Front Immunol 15:1346749. doi:10.3389/fimmu.2024.1346749 PubMed DOI PMC

Escalera A, Rojo-Fernandez A, Rombauts A, Abelenda-Alonso G, Carratalà J, García-Sastre A, Aydillo T. 2024. SARS-CoV-2 infection induces robust mucosal antibody responses in the upper respiratory tract. i Science 27:109210. doi:10.1016/j.isci.2024.109210 PubMed DOI PMC

Conner TL, Goguet E, Haines-Hull H, Segard A, Darcey ES, Kobi P, Balogun B, Olsen C, Esposito D, Jones M, Burgess TH, O’Connell RJ, Broder CC, Saunders D, Pollett S, Laing ED, Mitre E. 2024. Subclinical SARS-CoV-2 infections and endemic human coronavirus immunity shape SARS-CoV-2 saliva antibody responses. medRxiv. doi:10.1101/2024.05.22.24307751 DOI

Wright PF, Prevost-Reilly AC, Natarajan H, Brickley EB, Connor RI, Wieland-Alter WF, Miele AS, Weiner JA, Nerenz RD, Ackerman ME. 2022. Longitudinal systemic and mucosal immune responses to SARS-CoV-2 infection. J Infect Dis 226:1204–1214. doi:10.1093/infdis/jiac065 PubMed DOI PMC

Mettelman RC, Allen EK, Thomas PG. 2022. Mucosal immune responses to infection and vaccination in the respiratory tract. Immunity 55:749–780. doi:10.1016/j.immuni.2022.04.013 PubMed DOI PMC

Fröberg J, Gillard J, Philipsen R, Lanke K, Rust J, van Tuijl D, Teelen K, Bousema T, Simonetti E, van der Gaast-de Jongh CE, Bos M, van Kuppeveld FJ, Bosch B-J, Nabuurs-Franssen M, van der Geest-Blankert N, van Daal C, Huynen MA, de Jonge MI, Diavatopoulos DA. 2021. SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nat Commun 12:5621. doi:10.1038/s41467-021-25949-x PubMed DOI PMC

Chan RWY, Chan KCC, Lui GCY, Tsun JGS, Chan KYY, Yip JSK, Liu S, Yu MWL, Ng RWY, Chong KKL, Wang MH, Chan PKS, Li AM, Lam HS. 2022. Mucosal antibody response to SARS-CoV-2 in paediatric and adult patients: a longitudinal study. Pathogens 11:397. doi:10.3390/pathogens11040397 PubMed DOI PMC

Wagstaffe HR, Thwaites RS, Reynaldi A, Sidhu JK, McKendry R, Ascough S, Papargyris L, Collins AM, Xu J, Lemm N-M, Siggins MK, Chain BM, Killingley B, Kalinova M, Mann A, Catchpole A, Davenport MP, Openshaw PJM, Chiu C. 2024. Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults. Sci Immunol 9:eadj9285. doi:10.1126/sciimmunol.adj9285 PubMed DOI

Hu Z, López-Muñoz AD, Kosik I, Li T, Callahan V, Brooks K, Yee DS, Holly J, Santos JJS, Castro Brant A, Johnson RF, Takeda K, Zheng Z-M, Brenchley JM, Yewdell JW, Fox JM. 2024. Recombinant OC43 SARS-CoV-2 spike replacement virus: an improved BSL-2 proxy virus for SARS-CoV-2 neutralization assays. Proc Natl Acad Sci USA 121:e2310421121. doi:10.1073/pnas.2310421121 PubMed DOI PMC

Lim JME, Tan AT, Le Bert N, Hang SK, Low JGH, Bertoletti A. 2022. SARS-CoV-2 breakthrough infection in vaccinees induces virus-specific nasal-resident CD8+ and CD4+ T cells of broad specificity. J Exp Med 219:e20220780. doi:10.1084/jem.20220780 PubMed DOI PMC

Wang CC, Prather KA, Sznitman J, Jimenez JL, Lakdawala SS, Tufekci Z, Marr LC. 2021. Airborne transmission of respiratory viruses. Science 373:eabd9149. doi:10.1126/science.abd9149 PubMed DOI PMC

Prentiss M, Chu A, Berggren KK. 2022. Finding the infectious dose for COVID-19 by applying an airborne-transmission model to superspreader events. PLOS One 17:e0265816. doi:10.1371/journal.pone.0265816 PubMed DOI PMC

Sidik S. 2023. ‘Bold’ study that gave people COVID reveals ‘supershedder’ phenomenon. Nature 618:892–893. doi:10.1038/d41586-023-01961-7 PubMed DOI

Steiner S, Kratzel A, Barut GT, Lang RM, Aguiar Moreira E, Thomann L, Kelly JN, Thiel V. 2024. SARS-CoV-2 biology and host interactions. Nat Rev Microbiol 22:206–225. doi:10.1038/s41579-023-01003-z PubMed DOI

Taylor HP, Dimmock NJ. 1985. Mechanism of neutralization of influenza virus by secretory IgA is different from that of monomeric IgA or IgG. J Exp Med 161:198–209. doi:10.1084/jem.161.1.198 PubMed DOI PMC

Renegar KB, Jackson GDF, Mestecky J. 1998. In vitro comparison of the biologic activities of monoclonal monomeric IgA, polymeric IgA, and secretory IgA. J Immunol 160:1219–1223. PubMed

Sun L, Kallolimath S, Palt R, Stiasny K, Mayrhofer P, Maresch D, Eidenberger L, Steinkellner H. 2021. Increased in vitro neutralizing activity of SARS-CoV-2 IgA1 dimers compared to monomers and IgG. Proc Natl Acad Sci USA 118:e2107148118. doi:10.1073/pnas.2107148118 PubMed DOI PMC

Wang Z, Lorenzi JCC, Muecksch F, Finkin S, Viant C, Gaebler C, Cipolla M, Hoffmann H-H, Oliveira TY, Oren DA, Ramos V, Nogueira L, Michailidis E, Robbiani DF, Gazumyan A, Rice CM, Hatziioannou T, Bieniasz PD, Caskey M, Nussenzweig MC. 2021. Enhanced SARS-CoV-2 neutralization by dimeric IgA. Sci Transl Med 13:eabf1555. doi:10.1126/scitranslmed.abf1555 PubMed DOI PMC

Pande K, Hollingsworth SA, Sam M, Gao Q, Singh S, Saha A, Vroom K, Ma XS, Brazell T, Gorman D, Chen S-J, Raoufi F, Bailly M, Grandy D, Sathiyamoorthy K, Zhang L, Thompson R, Cheng AC, Fayadat-Dilman L, Geierstanger BH, Kingsley LJ. 2022. Hexamerization of anti-SARS CoV IgG1 antibodies improves neutralization capacity. Front Immunol 13:864775. doi:10.3389/fimmu.2022.864775 PubMed DOI PMC

Woof JM, Russell MW. 2011. Structure and function relationships in IgA. Muc Immunol 4:590–597. doi:10.1038/mi.2011.39 PubMed DOI

Bidgood SR, Tam JCH, McEwan WA, Mallery DL, James LC. 2014. Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells. Proc Natl Acad Sci USA 111:13463–13468. doi:10.1073/pnas.1410980111 PubMed DOI PMC

Mestecky J, Russell MW. 1986. IgA subclasses. Monogr Allergy 19:277–301. PubMed

Mestecky J, Woof JM. 2015. Mucosal immunoglobulins, p 287–347. In Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroutre H, Lambrecht BN (ed), Mucosal immunology, 4th edition. Academic Press/Elsevier, Amsterdam.

Pietrasanta C, Darwich A, Ronchi A, Crippa B, Spada E, Mosca F, Pugni L, Rescigno M. 2022. Humoral response to anti-SARS-CoV-2 vaccine in breastfeeding mothers and mother-to-infant antibody transfer through breast milk. NPJ Vaccines 7:63. doi:10.1038/s41541-022-00499-5 PubMed DOI PMC

Kilian M, Mestecky J, Russell MW. 1988. Defense mechanisms involving Fc-dependent functions of immunoglobulin A and their subversion by bacterial immunoglobulin A proteases. Microbiol Rev 52:296–303. doi:10.1128/mr.52.2.296-303.1988 PubMed DOI PMC

Underdown BJ, Dorrington KJ. 1974. Studies on the structural and conformational basis for the relative resistance of serum and secretory immunoglobulin A to proteolysis. J Immunol 112:949–959. PubMed

Crottet P, Corthésy B. 1998. Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab’)2: a possible implication for mucosal defense. J Immunol 161:5445–5453. PubMed

Kilian M, Russell MW. 2015. Microbial evasion of IgA functions, p 455–470. In Mestecky J, Strober W, Russell MW, Kelsall BL, Cheroutre H, Lambrecht BN (ed), Mucosal immunology, 4th edition. Academic Press/Elsevier, Amsterdam.

Kilian M, Reinholdt J, Lomholt H, Poulsen K, Frandsen EVG. 1996. Biological significance of IgA1 proteases in bacterial colonization and pathogenesis: critical evaluation of experimental evidence. APMIS 104:321–338. doi:10.1111/j.1699-0463.1996.tb00724.x PubMed DOI

Russell MW, Reinholdt J, Kilian M. 1989. Anti-inflammatory activity of human IgA antibodies and their Fabalpha fragments: inhibition of IgG-mediated complement activation. Eur J Immunol 19:2243–2249. doi:10.1002/eji.1830191210 PubMed DOI

Weiser JN, Bae D, Fasching C, Scamurra RW, Ratner AJ, Janoff EN. 2003. Antibody-enhanced pneumococcal adherence requires IgA1 protease. Proc Natl Acad Sci USA 100:4215–4220. doi:10.1073/pnas.0637469100 PubMed DOI PMC

Kilian M, Husby S, Andersen J, Moldoveanu Z, Sørensen UBS, Reinholdt J, Tettelin H. 2022. Induction of susceptibility to disseminated infection with IgA1 protease-producing encapsulated pathogens Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. MBio 13:e0055022. doi:10.1128/mbio.00550-22 PubMed DOI PMC

Mehta SK, Plaut AG, Calvanico NJ, Tomasi TB. 1973. Human immunoglobulin A: production of an Fc fragment by an enteric microbial proteolytic enzyme. J Immunol 111:1274–1276. PubMed

Murphy TF, Kirkham C, Jones MM, Sethi S, Kong YY, Pettigrew MM. 2015. Expression of IgA Proteases by Haemophilus influenzae in the Respiratory Tract of Adults With Chronic Obstructive Pulmonary Disease. J Infect Dis 212:1798–1805. doi:10.1093/infdis/jiv299 PubMed DOI PMC

Parker AM, Jackson N, Awasthi S, Kim H, Alwan T, Wyllie AL, Baldwin AB, Brennick NB, Moehle EA, Giannikopoulos P, Kogut K, Holland N, Mora AM, Eskenazi B, Riley LW, Lewnard JA. 2023. Association of upper respiratory Streptococcus pneumoniae colonization with severe acute respiratory syndrome coronavirus 2 infection among adults. Clin Infect Dis 76:1209–1217. doi:10.1093/cid/ciac907 PubMed DOI

Romani L, Del Chierico F, Pane S, Ristori MV, Pirona I, Guarrasi V, Cotugno N, Bernardi S, Lancella L, Perno CF, et al. . 2024. Exploring nasopharyngeal microbiota profile in children affected by SARS-CoV-2 infection. Microbiol Spectr 12:e03009–23. doi:10.1128/spectrum.03009-23 PubMed DOI PMC

Mitsi E, Reiné J, Urban BC, Solórzano C, Nikolaou E, Hyder-Wright AD, Pojar S, Howard A, Hitchins L, Glynn S, et al. . 2022. Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2. J Clin Invest 132:e157124. doi:10.1172/JCI157124 PubMed DOI PMC

Missa KF, Diallo K, Bla KB, Tuo KJ, Gboko KDT, Tiémélé L-S, Ouattara AF, Gragnon BG, Ngoi JM, Wilkinson RJ, Awandare GA, Bonfoh B. 2024. Association of symptomatic upper respiratory tract infections with the alteration of the oropharyngeal microbiome in a cohort of school children in Côte d’Ivoire. Front Microbiol 15:1412923. doi:10.3389/fmicb.2024.1412923 PubMed DOI PMC

Find record

Citation metrics

Loading data ...

Archiving options

Loading data ...