BACTERIAL INTERFERENCE TO PREVENT STAPHYLOCOCCUS AUREUS INFECTION

PROJECT SUMMARYAlthough Staphylococcus aureus is a major human pathogen that causes an enormousburden of disease, we have very few strategies for preventing infection or controlling itsspread. In the 1960's it was a widespread practice to inoculate neonates with a relativelybenign strain of S. aureus called 502A as a strategy to combat outbreaks of morevirulent staphylococcal strains, a practice referred to as bacterial interference.Thousands of neonates were exposed to 502A with very little associated morbidity andmortality, but despite its relatively good safety record, the practice was abandoned in the1970's due to safety concerns. The basic mechanisms of bacterial interference werenever investigated. We recently showed that 502A elicits a very different cytokineresponse compared to other epidemic and virulent strains. Although it is less invasive,host cells exposed to 502A have increased levels of type I Interferons as well as severalother proinflammatory cytokines (eg., TNFa, IL-6) compared to exposure to other S.aureus strains. Our hypothesis is that S. aureus strains that stimulate 502A-likeimmune responses protect from colonization and subsequent infection byinducing the immune system to reject other strains. Understanding the mechanismof 502A bacterial interference could allow us to design strategies for protection againstcolonization and infection with virulent or antibiotic resistant strains. It may also lead tostrategies for decolonization in the setting of recurrent S. aureus infection or in intensivecare units where universal decolonization using antimicrobials has been show todecrease mortality. We combine a clinical approach with basic molecular research,aiming to assess the feasibility of a bacterial interference strategy in the clinical context.The study team integrates expertise in clinical S. aureus epidemiology, host innateimmunology, and genomics and microbiome studies. Aim 1 uses the natural diversity inS. aureus strains found in human populations to prospectively assess the correlation ofcolonization with 502A-like strains and possible protection. Aim 2 uses model systemsto assess the response of the immune system to 502A-like strains as well as theirprotective effect. Aim 3 examines the possibility of using a virulence-attenuated strainfor bacterial interference and decolonization.