Eric G. Pamer: VRE Colonization and Infection

Figure 1 Enlarge Image Figure 1

Antibiotic-resistant bacteria are an increasing problem in hospitalized patients and commonly cause infections following broad-spectrum antibiotic administration. Among these, Vancomycin-resistant Enterococcus (VRE), is one of the most common causes of bloodstream infections. Commensal microbes that colonize mucosal surfaces provide defense against infection by physically occupying niches and competing for nutrients. In addition, commensal microbes also condition the intestinal mucosa to resist bacterial invasion by inducing expression of antimicrobial molecules. Clinical use of antibiotics profoundly alters the commensal flora by selectively killing subsets of microbes that are normal intestinal inhabitants. The downstream effects of antibiotic-induced microbial depletion on mucosal innate immune defenses remain largely undefined. Our laboratory is testing the hypothesis that antibiotic therapy, by depleting commensal microbes, compromises intestinal innate immune defenses and increases vulnerability to infection by antibiotic resistant microbes.

Our laboratory demonstrated that treatment of mice with antibiotics dramatically increases susceptibility to colonization with VRE (Figure 1).

Antibiotic administration also decreases expression of RegIIIγ, a bactericidal C-type lectin that is secreted by intestinal epithelial cells. RegIIIγ kills VRE in the ileum of mice and decreased expression of RegIIIγ during antibiotic treatment increases susceptibility to VRE colonization (Figure 2).

Figure 2 Enlarge Image Figure 2

Our laboratory has demonstrated that oral administration of lipopolysaccharide (LPS), a ligand for TLR4, or systemic administration of flagellin, a ligand for TLR5, reverses antibiotic-induced down-regulation of RegIIIγ and enhances resistance to colonization with VRE.

Ongoing studies in our laboratory are investigating the cellular mechanisms of TLR-mediated colonization resistance. While induction of IL22 is essential for the expression of RegIIIγ by intestinal epithelial cells, the cell populations and networks in the lamina propria of the gut that orchestrate antimicrobial defenses on the mucosal surface remain mysterious.