Staphylococcus aureus (S. aureus) is a major cause of skin and soft tissue infections that can sometimes lead to sepsis and toxic shock syndrome. The microbe poses a significant threat to public health, made worse by the spread of methicillin-resistant Staphylococcus aureus bacteria (MRSA) in recent years. According to The Lancet, S. aureus was associated with more than one million deaths around the globe in 2019.
“It is a pathogen in dire need of control because it causes significant morbidity and mortality not just in the United States, but worldwide,” said George Liu, M.D., Ph.D., professor of and chief of pediatric infectious diseases at University of California San Diego School of Medicine and Rady Children’s Hospital-San Diego.
Yet, despite working well in mouse models, approximately 30 clinical trials to date have failed to result in an effective human vaccine for S. aureus. Now, UC San Diego researchers have identified a key reason for these failures, indicating that it may be possible to modify the vaccines to work in humans. In a study published on December 16, 2024 in the Journal of Clinical Investigation (JCI), they report that S. aureus induces an overabundance of a protein called interleukin-10 (IL-10) in B cells, leading to the inactivation of antibodies, rendering them unable to kill S. aureus.
In a related study published the same day in Nature Communications, UC San Diego School of Medicine researchers also found that an overabundance of IL-10 in response to S. aureus shuts down the ability of helper T cells to fight the pathogen.
Liu says S. aureus shares a long history with humans. “For a bacterium to readily live in our nose and gut, it needs to develop a strategy that effectively dampens the immune response to be able to survive.”
In infancy, the majority of us are colonized with S. aureus, which hitches a ride in our nasal passages. For the most part, it doesn’t harm us. But a previous study from 2022, led by Chih-Ming Tsai, Ph.D., an assistant project scientist in Liu’s lab, showed that this early exposure fools our immune cells into producing modified antibodies that fail to mount an effective defense against S. aureus. What’s more, the bacteria retain a “memory” of those non-protective antibodies that can be brought back during later infections.
Tsai says that’s why vaccine candidates that have worked well in mice with no previous exposure to the pathogen have failed to protect humans from new encounters with S. aureus. However, when the researchers exposed mice to human S. aureus antibodies before vaccination to replicate our early experience with the bacteria, the vaccine no longer worked.
B cells
In the JCI study, Tsai, Liu, and their team sought to understand what renders the S. aureus antibodies useless at fighting the pathogen after vaccination. The researchers exposed mice to S. aureus, and later inoculated them with Iron Surface Determinant B (IsdB) vaccine, which had previously been shown to confer immunity to S. aureus in mice that were naive to the bacteria.
The team found that B cells — white blood cells that make antibodies — secrete an abundance of IL-10 when challenged with S. aureus for a second time. Within the B cells, IL-10 directs the enzymes to add a sugar called sialic acid to the Fc region of the antibodies — the region responsible for generating an appropriate immune response. With the sugar abundantly present, the anti-staphylococcal activity of antibodies produced by the B cells is neutralized, making them incapable of killing the pathogen.
“The IL-10 is helping make tons of this sugar type and by doing so, it’s turning off our immune system,” said Tsai. However, the researchers also found that blocking IL-10 at the time of immunization restores vaccine efficacy. “The same vaccine that didn’t work before now works perfectly in mice,” he added.
T cells
While the JCI study focused on the role of IL-10 in B cells, the Nature Communications paper, led by first author Irshad A. Hajam, Ph.D., an assistant project scientist in Liu’s lab, examined how S. aureus interacts with CD4+ T lymphocytes, also known as helper T cells. These are white blood cells that detect infections and activate other immune cells to attack and kill pathogens.
The researchers found that like B cells, helper T cells also secrete an overabundance of IL-10 in response to S. aureus in mice previously exposed to and later vaccinated for S. aureus.
IL-10 shuts down the ability of the helper T cells to produce interleukin-17 (IL-17A), a cytokine that is particularly effective at fighting S. aureus infections. But by blocking IL-10 or adding a substance called CAF01 — known to enhance vaccine efficacy by increasing the response of T cells to microbial infections — the researchers were able to restore IL-17A levels.
“Adding CAF01 during vaccination helped turn the ineffective IsdB vaccine into one that worked in S. aureus-exposed mice,” said Hajam. “Surprisingly, it also worked with several other failed vaccines against S. aureus.”
The findings from both studies could be good news for human S. aureus vaccine development. Liu says it may be possible to make already-developed but failed S. aureus vaccines effective by blocking IL-10 or boosting IL-17A during vaccination. He adds that IL-10 production by a number of other microbes including (Clostridioides difficile and malaria) could be a reason why promising vaccines for these conditions have failed in human clinical trials, suggesting that blocking the cytokine could restore their efficacy as well.
Additional co-authors on the JCI study include: Irshad A. Hajam, J.R. Caldera, Biswa Choudhury, Cesia Gonzalez, Xin Du, Brian Lin, Haining Li, Ty’Tianna Clark, Fatemeh Askarian, Igor Wierzbicki, Emi Suzuki, Conrad J. Douglas, David J. Gonzalez, Victor Nizet, Nathan E. Lewis, all at UC San Diego School of Medicine; Angelica M. Riestra at San Diego State University; and Austin W.T. Chiang at Augusta University.
The JCI study was funded, in part, by the National Institutes of Health (grants R01AI127406, R01AI144694, R01AI181321, R01AI179098 and R35 GM119850) and the Novo Nordisk Foundation (NNF20SA0066621).
