An international collaboration of researchers in Europe and the U.S. has identified a critical immune factor for host defense against Staphylococcus aureus, which could offer a potential explanation for the failure of previous vaccine strategies, and point to new strategies against the bacterium.
The team, including researchers at Amsterdam University Medical Center (UMC), in collaboration with UMC Utrecht, Leiden University, and the University of California, San Diego, found that healthy humans generate both IgM and IgG antibodies against a particular S. aureus surface sugar, with lab tests showing that the IgM antibodies were significantly more effective at killing the bacteria than were the IgG antibodies. In a clinical setting, patients with S. aureus bacteremia had significantly lower levels of IgM but similar IgG levels compared to healthy controls. Importantly, low levels of the IgM antibodies among patients with S. aureus bacteremia correlated with disease mortality and impaired cell killing.
“Our findings directly challenge the current way of thinking about staphylococcal infections,” said Nina van Sorge, professor of translational microbiology at Amsterdam UMC. “It is generally assumed that the recognition of S. aureus by IgG antibodies, which helps immune cells to kill Staph, is key to offering protection. In this study we propose that this might not be the answer. We show that not IgG, but IgM antibodies are required for clearance of S. aureus during an infection.”
The team reported on its findings in Cell Reports Medicine, in a paper titled “Glycan-specific IgM is critical for human immunity to Staphylococcus aureus. In their paper the team reported, “Our findings may guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S. aureus infection.”
Staphylococcus aureus is among the leading causes of both community- and hospital-acquired infections. The authors cite data indicating that antibiotic-resistant methicillin-resistant Staphylococcus aureus (MRSA) killed around 120,000 people in 2022 globally, and far more are killed by antibiotic-susceptible strains of S. aureus. So far, attempts at developing a protective vaccine for S. aureus have been unsuccessful. Therapeutic antibodies and vaccines targeting surface antigens that have shown promise in animal models have “consistently failed” in human testing, the authors noted. “To improve future clinical outcomes, improved risk stratification as well as the development of alternative strategies, such as vaccines and immune-based approaches, is imperative,” they commented. However, “a precise understanding of the immune correlates responsible for protection against S. aureus remains elusive.”
The newly reported research has uncovered an important immune component that offers protection against infection, suggesting a new direction for the future. The research team, led by van Sorge and postdoc Astrid Hendriks, PhD, explored the presence of S. aureus-recognizing antibodies in the blood of healthy individuals. They focused on particular sugars that form a sort of sugar coat around the bacterium. They found that almost all healthy individuals had both IgG and IgM antibodies that could recognize these S. aureus surface glycan wall teichoic acids (WTAs). “We all have high antibody levels against the S. aureus sugar coat, since we are exposed to this bacterium multiple times throughout our lives without getting ill,” Hendriks said. “Yet we don’t know which antibodies are in fact preventing us from getting ill.”
The team’s studies found that, in a lab setting, IgM antibodies were significantly more effective at killing the bacteria than IgG. “IgG antibodies offer protection against bacterial pathogens in general and are actually critical for the protective effect of vaccines against for example pneumococcal and meningococcal infections. But for S. aureus, it is more complex,” von Sorge added. “This clever bacterium has developed ways to circumvent our defense system, and in particular IgG antibodies, which is part of the reason that it still causes so many problems.” However, researchers found that S. aureus did not counter the effects of IgM.
They in addition discovered that patients with life-threatening S. aureus bloodstream infections had much lower levels of sugar coat-specific IgM antibodies in their blood than healthy individuals. Importantly, those patients who did not survive the infection had the lowest levels of IgM antibodies. The researchers hypothesized that insufficient levels of sugar-specific IgM antibodies increase the risk of serious staphylococcal infections, and even mortality. Although more research is needed to validate this hypothesis, the newly reported findings provide insights that may shape future development of vaccines and other immune-boosting therapies.
In their paper the investigators concluded, “Our findings suggest that IgM plays a critical role in protecting against severe S. aureus infections, challenging the notion that it is merely a transitional antibody isotype … Based on our data, low WTA-specific IgM titers may be a risk factor for the development of S. aureus bacteremia and poor clinical outcomes.” The team stressed that further experimental and clinical studies will be needed to assess the generalizability of their findings.
They note that their findings may have important implications for risk assessment and prophylaxis for hospitalized patients. “Conceivably, patients with a planned procedure that holds risk for opportunistic S. aureus infections could be evaluated for WTA-specific IgM titers, similar to the assessment of other risk factors such as neutrophil counts and S. aureus colonization, which clinicians could weigh in decisions on antibiotic selection or frequency of monitoring,” they wrote. Future studies could also look at potential prophylactics or therapeutic application of polyclonal or monoclonal IgM to improve outcomes in patients with S. aureus bacteremia, they suggested.
