Research ArticleInfectious Disease

TLR-7 activation enhances IL-22–mediated colonization resistance against vancomycin-resistant enterococcus

Science Translational Medicine  24 Feb 2016:
Vol. 8, Issue 327, pp. 327ra25
DOI: 10.1126/scitranslmed.aad6663

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Combating antibiotic resistance

Antibiotics are the front line of defense against many bacterial infections, but antibiotics also disrupt the intestinal microbiota, which provides a barrier against colonization by other pathogens, such as vancomycin-resistant Enterococcus faecium (VRE). Abt et al. now find that a synthetic ligand for Toll-like receptor 7 stimulates antiviral innate immune responses in the intestine similar to viral infection, restoring colonization resistance to VRE. Thus, this orally bioavailable therapy may serve to limit infection by intestinal pathogens in antibiotic-exposed, susceptible individuals.

Abstract

Antibiotic administration can disrupt the intestinal microbiota and down-regulate innate immune defenses, compromising colonization resistance against orally acquired bacterial pathogens. Vancomycin-resistant Enterococcus faecium (VRE), a major cause of antibiotic-resistant infections in hospitalized patients, thrives in the intestine when colonization resistance is compromised, achieving extremely high densities that can lead to bloodstream invasion and sepsis. Viral infections, by mechanisms that remain incompletely defined, can stimulate resistance against invading bacterial pathogens. We report that murine norovirus infection correlates with reduced density of VRE in the intestinal tract of mice with antibiotic-induced loss of colonization resistance. Resiquimod (R848), a synthetic ligand for Toll-like receptor 7 (TLR-7) that stimulates antiviral innate immune defenses, restores expression of the antimicrobial peptide Reg3γ and reestablishes colonization resistance against VRE in antibiotic-treated mice. Orally administered R848 triggers TLR-7 on CD11c+ dendritic cells, inducing interleukin-23 (IL-23) expression followed by a burst of IL-22 secretion by innate lymphoid cells, leading to Reg3γ expression and restoration of colonization resistance against VRE. Our findings reveal that an orally bioavailable TLR-7 ligand that stimulates innate antiviral immune pathways in the intestine restores colonization resistance against a highly antibiotic-resistant bacterial pathogen.

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