# Examining the role of IgA in a persistent model of Staphylococcus aureus colonization

## TL;DR

The study explores how Staphylococcus aureus uses IgA to persist in the host and finds that IgA deficiency can lead to faster bacterial clearance.

## Contribution

The study reveals that S. aureus exploits SIgA via SpA for colonization and that IgA deficiency enhances bacterial clearance through Th1 responses.

## Key findings

- IgA-deficient mice show reduced S. aureus burdens and faster decolonization compared to wild-type mice.
- SpA binds IgA to promote colonization, and its absence or IgA deficiency leads to increased IgG2c/IgG1 ratios and Th1 responses.
- Vaccination against SpA accelerates decolonization in IgA-deficient mice, suggesting Th1-mediated clearance.

## Abstract

Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. Nasal colonization occurs in the first weeks of life and persists in about 30% of the population. Using the mouse-adapted strain WU1 to model persistent colonization, we reported earlier that inoculation of bacteria lacking Staphylococcal protein A (SpA/Δspa) or neutralization of SpA through vaccination result in the slow decolonization of animals. Secretory (S)IgA is considered a first line of defense against pathogens at mucosal surfaces. Here, we use Ighasec-/- mutant mice to evaluate the contribution of SIgA towards decolonization. We observe that WU1 burdens are reduced in colonized Ighasec-/- mice compared to C57BL/6J animals. Both C57BL/6J and Ighasec-/- mice eliminate Δspa bacteria, yet elimination occurs more rapidly in animals lacking IgA. SpA captures Fab-VH3-type antibodies, including IgA, on the bacterial cell surface. We propose that this activity promotes colonization. Yet, we also find that antibody responses to the pathogen are altered when SpA and IgA are missing. Colonized C57BL/6J mice display a low serum IgG2c/IgG1 ratio towards staphylococcal antigens. This ratio is increased in animals colonized with Δspa and is further enhanced in Ighasec-/- mice. We attribute the former to the loss of immune evasion activity in absence of SpA, and the latter to a host compensatory mechanism upon exposure to S. aureus. Importantly, the increased IgG2c/IgG1 ratio correlates with decolonization and enhanced killing of S. aureus. Similarly, we observe that decolonization induced by SpA-vaccination is accelerated in Ighasec-/- mice which display higher anti-SpA IgG2c titers as compared to C57BL/6J animals. Together, these findings suggest that S. aureus exploits SIgA in a SpA-dependent manner for colonization and in absence of IgA, serum opsonizing antibodies may promote bacterial clearance at mucosal surfaces.

The mucosa is constantly exposed to microbes keeping it clear of pathogens while tolerating those beneficial to the host. Secretory immunoglobulin A (SIgA) contributes to such homeostasis by inhibiting microbial attachment, neutralizing toxins, and controlling inflammatory responses at mucosal surfaces. Yet, Staphylococcus aureus, a deadly pathogen, colonizes the upper respiratory track of humans asymptomatically. This behavior suggests that S. aureus subverts mucosal immune responses. Here, we compare S. aureus colonization in wild type and mice lacking IgA. We find that while colonization is not strictly impaired, bacterial burdens in IgA deficient animals are reduced. Staphylococcal protein A (SpA), a protein that coats the bacterial surface and binds antibodies takes advantage of IgA for colonization. In absence of bacterial SpA or host IgA, animals develop a high ratio of IgG2c/IgG1 against S. aureus indicative of a Th1 response. In absence of both SpA and IgA, this response is further expanded and correlates with a slow but steady loss of S. aureus carriage. In a vaccination approach aimed at neutralizing the immune suppressive activities of SpA, animals lacking IgA undergo accelerated decolonization compared to wild type animals. These findings suggest that S. aureus exploits SIgA during colonization, SIgA antibodies are not required for vaccine-mediated decolonization, and serum opsonizing antibodies elicited by the Th1 response may promote bacterial clearance at mucosal surfaces.