Glycan-specific IgM is critical for human immunity to Staphylococcus aureus

Background

Staphylococcus aureus, a bacterial pathogen, is responsible for numerous community- and hospital-acquired infections, many of which are caused by antibiotic-resistant strains. The growing challenge of antibiotic resistance necessitates the exploration of alternative approaches to improve clinical outcomes in treating bacterial infections.

Neutrophils are immune cells that phagocytose invading bacteria. To facilitate their recognition and engulfment of these pathogens, additional immune factors such as antibodies and complement proteins act as opsonins, marking the bacterium for phagocytosis. Despite extensive efforts, the identification of opsonizing IgG antibodies targeting S. aureus has been met with limited success in human clinical trials. This might be due to a protein found on S. aureus, staphylococcal protein A (SpA), which inhibits the efficacy of IgG opsonization. However, IgG antibodies are not the sole contributors to enhanced neutrophil activity. IgM antibodies may be able to not only bind S. aureus but also remain unaffected by SpA. Up to this point, research focused on IgM antibodies has been relatively limited since they are conventionally considered to be merely undifferentiated prototype antibodies.

 

Summary

WTA-specific IgM antibodies were more effective than IgG antibodies in vitro

In this study, the researchers utilized synthetic S. aureus wall teichoic acids (WTAs) to study how different kinds of antibodies target the three WTA glycotypes found in S. aureus. WTAs are conserved cell-wall anchored glycopolymers that are a target for opsonizing antibodies. The plasma of healthy donors was found to contain IgM antibodies that bound to all three WTA glycotypes. Next, the researchers compared the efficiency of both IgM and IgG antibodies and found that the IgM variant was over 100-fold more effective than the IgG variant at inducing complement deposition on S. aureus. They also found that the presence of SpA did not interfere with IgM-mediated complement deposition. This complement deposition triggered neutrophil-mediated killing of S. aureus in the presence of IgM antibodies but did not occur in the presence of IgG antibodies.

WTA-specific IgM antibodies were more effective than IgG antibodies in mice

Next, the researchers passively immunized mice with WTA-specific IgM prior to S. aureus infection. The IgM-treated mice had significantly lower CFU counts of bacteria in their spleens as compared to control groups treated with PBS or a non-specific IgM antibody, showing that WTA-specific IgM plays a critical role in conferring protection against S. aureus infection.

Above: a) Complement deposition on wild type (WT) S. aureus or SpA-deficient (Δspa) S. aureus, pre-opsonized with either WTA-specific IgM or IgG. Note that IgG requires a much higher concentration than IgM to deposit the same amount of complement protein. b) Relative complement deposition on SpA-deficient S. aureus, pre-opsonized with either WTA-specific IgM or IgG in the presence of various concentrations of recombinant SpA. Note that IgG is inhibited by increasing concentrations of SpA, while IgM is unaffected. c) Neutrophil killing of S. aureus in the presence of WTA-specific IgM, WTA-specific IgG, or no antibody control. Note that the % of bacteria survival in the presence of IgG is not significantly different from bacteria with no antibody present, whereas IgM results in significantly fewer bacteria that survived. d) Spleen CFU counts from mice at 24 h post-infection. Mice have been passively immunized with either WTA-specific IgM, anti-TNP IgM (as an isotype control), or a PBS control. Mice that were given a control (either PBS or control antibody) had more bacteria in their spleens than mice that received a WTA-specific IgM treatment. Each of these experiments demonstrates that IgM is effective against S. aureus bacteria.

WTA-specific IgM antibodies were reduced in human ICU patients with S. aureus bacteremia

The researchers also tested a cohort of 36 ICU patients with S. aureus bacteremia. They observed that IgG responses to any of the three WTA glycotypes were comparable between healthy donors and patients with bacteremia. However, the patients infected with S. aureus had significantly reduced WTA-specific IgM when compared to healthy donors or patients infected with Streptococcus pyogenes. In addition, IgM levels against the TarS and TarM glycotypes of WTA were significantly lower in deceased patients than in those who recovered.

 

Conclusion

This research sheds light on the crucial role of WTA-specific IgM antibodies in protection against S. aureus infections. The study’s findings challenge the conventional focus on IgG antibodies and suggest that efforts to boost durable opsonic IgM responses through vaccination may hold promise in preventing severe S. aureus infections. The identification of WTA-specific IgM as a significant protective factor can inform risk stratification for hospitalized patients and guide the design of antibody-based therapies and vaccines against this major human pathogen.

What I liked about this preprint

This preprint caught my attention because of its focus on IgM antibodies, which are often overlooked in favor of the more differentiated IgG antibodies. With the rising challenge of antibiotic-resistant bacteria, it is crucial to explore alternative treatment methods and vaccination strategies.

Questions for the authors

1. Was there any correlation between the site of S. aureus infection and patient IgM levels?
2. Do you have any hypotheses as to why patient IgM levels were decreased in patients with S. aureus bacteremia but not S. pyogenes bacteremia?
3. It looks as though the TarP glycotype may be less affected by IgM treatment than the TarS or TarM glycotypes. Do you have a hypothesis as to why this might be the case? Does this have implications for the effectiveness of a future WTA-specific IgM-based treatment?

Tags: antibodies, staphylococcus aureus

Posted on: 10 August 2023 , updated on: 11 August 2023

doi: https://doi.org/10.1242/prelights.35297

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