According to researchers at the University of California, San Francisco (UCSF), a specific toxin made by Staphylococcus aureus plays a role in preventing tolerance and maintaining the immune system’s vigilance in the skin of newborns.
Results of a mouse-model study were published online ahead of print in Cell Host & Microbe (Nov. 26, 2019).
Prior research conducted by a team led by Dr. Tiffany Scharschmidt, an associate professor in the department of dermatology at UCSF, showed that exposure to healthy bacteria as a newborn led to immune tolerance: limiting skin inflammation upon subsequent encounters with this species. In contrast, delaying initial exposure to S. epidermidis until later in life resulted in a more inflammatory immune response to the same bacteria.
Researchers discovered that this early window for tolerance was supported by a class of immune cells called regulatory T cells (Tregs), known to play a role in maintaining tolerance to proteins from the body and in preventing autoimmune diseases.
They found that Tregs were enriched in neonatal skin compared to adult skin, which suggested the immune system could learn which bacterial species are “normal”, and likely healthy, based on which species Tregs encounter immediately after birth.
However, this hypothesis posed a new question: if a newborn is exposed to pathogenic bacteria, would their immune systems be tricked into welcoming these dangerous invaders with open arms? This conundrum led to the new study.
Dr. John Leech, the first author on the new study and postdoctoral researcher at UCSF, notes that S. aureus makes an array of toxins that can destroy host tissues or disrupt normal immune responses. But he found that one specific molecule, called alpha-toxin, allowed the immune system to recognize S. aureus as a threat during early-life skin exposure.
“Alpha toxin is the trigger that allows the immune system to say, ‘You’re not one of us,’” Dr. Leech said in a press release. “The immune system recognizes this pathogenic strain as one that is dangerous, and later in life it can still, mount a robust immune response against it.”
The study found that alpha-toxin prevented tolerance by triggering immune cells in the skin to take biochemical steps through an “alarmin pathway,” leading to the secretion of interleukin(IL)-1 beta. This resulted in a species-specific memory response involving fewer Tregs and instead, more immune cells poised to defend against S. aureus later in life.
“I am hopeful that learning how the immune system appropriately recognizes and responds to good bugs versus bad bugs will help us better understand why certain individuals are particularly susceptible to infection, or how chronic inflammatory skin disorders are apparently exacerbated by the presence of normally well-tolerated bacteria,” said Dr. Scharschmidt, who is also a member of the UCSF Benioff Center for Microbiome Medicine.
“It remains to be tested, but the types of immune responses we identified in this study are not unique to skin, and so I would think the same mechanisms of tolerance or lack of tolerance may hold for other body sites," she added.