SUMMARY
Our long-term objective is to find ways to control methicillin-resistant Staphylococcus aureus (MRSA). Here we
focus on characterizing how community-acquired (CA)-MRSA colonizes the gastrointestinal (GI) tract. A key, but
underappreciated, observation is that GI colonization establishes a reservoir for transmission and is the most
common origin for CA-MRSA infection in infants and young children, who are at greater risk of infection than
adults. We and others have used murine models to identify S. aureus traits that support GI colonization. However,
the mechanisms governing GI colonization relevant to CA-MRSA are poorly understood, in part due to the use
of animal models that rely on antibiotic depletion of gut microbiota to establish colonization. Our recent published
and unpublished work adapted an infant mouse model to provide a tractable system relevant to CA-MRSA GI
colonization in the community, especially among infants and children. Our preliminary data, obtained using this
model, show that weaning is associated with colonization resistance to CA-MRSA. We also show that pore-
forming leukotoxins (“toxins”) promote CA-MRSA colonization in weaned mice, but had no effect in infant mice
or germ-free adult mice. Given our finding that weaning was associated with colonization resistance to CA-
MRSA, a property thought to be conferred by commensal microbiota, we hypothesize that perturbation of
commensal bacteria by toxins empowers CA-MRSA to overcome colonization resistance by commensal
bacteria. We also established that colonization resistance against CA-MRSA is paradoxically increased in mice
that lack adaptive immunity (B and T cells). Given that innate immune cells that shape the gut microbiota during
weaning and confer resistance to pathogens are upregulated in such mice, we secondarily hypothesize that
innate immunity and the microbiota combine to inhibit CA-MRSA colonization. To test our hypotheses, we will 1)
identify commensal species that mediate CA-MRSA colonization resistance in the gut, 2) understand the immune
mechanisms that inhibit the CA-MRSA colonization in mice without adaptive immunity, and 3) determine the
specific CA-MRSA toxins and interactions between S. aureus and gut commensals that affect bacterial
competition. The outcomes of these studies promise to identify bacterial taxa, innate immune mechanisms, and
CA-MRSA loci we might manipulate to perturb CA-MRSA colonization. The results will guide future efforts to
identify microbiota and cell-type-specific targets for rationally designed therapeutic strategies that modulate
colonization. To the extent that the work identifies virulence factors that contribute directly to pathogen
transmission, our work will also uncover bacterial mechanisms that could be exploited as targets for dual-action
therapeutics.