What is it about?
An under-appreciated role of antibodies in secretions is their involvement in controlling the onward transmission of infectious agents. It is well recognized the secretory (S) IgA, which is the predominant form of antibody in mucosal secretions, serves as a front-line defense factor against the acquisition of infections. Airborne infections such as COVID are spread by droplets and aerosols emitted from infected individuals, and these emissions are derived from saliva and respiratory secretions. However, these are not merely passive vehicles of transmission, as they contain numerous host-derived immune factors, including SIgA antibodies, which have been shown to be far more effective in neutralizing viruses than other forms of antibodies, such as IgG that circulates in the blood. Human IgA1, which is the dominant subclass of SIgA in saliva and respiratory secretions, is susceptible to cleavage by unique IgA1 proteases elaborated by several bacteria found as commensals or pathogens of human mucosal tracts. We hypothesize that IgA1 proteases would compromise IgA1 antibody-mediated neutralization of viruses such as SARS-CoV-2, and not only render affected individuals more susceptible to serious disease, but also enhance their capacity to transmit the infection to other persons.
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Why is it important?
Onward transmission is a crucial aspect of infectious disease, and breaking the chains of transmission is critical for the control of epidemics. This can be accomplished by many interventions, including the use of anti-infectious drugs to reduce the burden of infectious agents, and vaccines to prevent infections in the first place. These interventions are primarily aimed at protecting individuals from the consequences of serious disease, but they also have a role in protecting communities through the principle of "herd immunity", whereby diminution of infection among individuals reduces the probability of transmission to others. An under-appreciated aspect of immunity is that it not only protects individuals from infectious disease, but also that it can reduce the infectivity of pathogens in the bodily secretions that serve as the vehicles of onward transmission. We propose an important role for secretory IgA, the predominant form of antibody in saliva and other secretions in diminishing the transmission of infections, and how this might be compromised by unique bacterial enzymes that cleave human SIgA1 antibodies to ineffective fragments.
Perspectives
This hypothesis was prompted by papers that demonstrated the substantial superiority of polymeric IgA antibodies (including secretory IgA) over monomeric IgA or IgG antibodies in neutralizing SARS-CoV-2, the virus that causes COVID. This finding implies that multivalent binding of polymeric antibodies, which increases their functional avidity, enhances viral neutralization. Conversely, it would be expected that monovalent fragments of antibodies, derived by enzymatic cleavage to Fab fragments, which retain intrinsic antigen-binding affinity, would have substantially less viral neutralizing activity than intact antibodies. A natural source of such fragments arises from bacterial IgA1 proteases that uniquely cleave human IgA1 (including SIgA1) to Fab-alpha and Fc-alpha (or Fc-alpha-secretory component) fragments. Several species of bacteria that produce such proteases are commonly found as commensals or pathogens in the human mouth and upper respiratory tract, and typical fragments of cleaved IgA have been identified in the secretions of subjects infected with these bacteria. We therefore hypothesized that SARS-CoV-2-infected subjects, who develop SIgA antibodies as a result of this infection, and also are colonized with IgA1-protease-producing bacteria, would show evidence of diminished IgA1-antibody-mediated neutralization of the virus, with consequences not only for diminished immune defense against COVID, but also enhancing their capacity to transmit the virus to others. This could be one factor contributing to "superspreader" status. We further suggest that this scenario could apply to other respiratory infections, such as influenza, which was originally attributed to Haemophilus influenzae before the virus was discovered. As H. influenzae produces IgA1 protease, it is conceivable that it might contribute to enhanced infectivity and transmission of influenza, thereby explaining the erroneous conclusion as to its causative involvement.
Professor Michael W Russell
University at Buffalo Department of Microbiology & Immunology
Read the Original
This page is a summary of: Role of IgA1 protease-producing bacteria in SARS-CoV-2 infection and transmission: a hypothesis, mBio, August 2024, ASM Journals,
DOI: 10.1128/mbio.00833-24.
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