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

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.

• Authors: Michael C Abt, Charlie G Buffie, Bože Sušac, Simone Becattini, Rebecca A Carter, Ingrid Leiner, James W Keith, David Artis, Lisa C Osborne, Eric G Pamer
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 327 Pg. 327ra25 (Feb 24 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 26912904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• CD11c Antigen
• Imidazoles
• Interferon Type I
• Interleukin-1
• Interleukin-23
• Interleukins
• Ligands
• Pancreatitis-Associated Proteins
• Proteins
• Reg3g protein, mouse
• Toll-Like Receptor 7
• Vancomycin
• Ampicillin
• resiquimod

Topics

• Ampicillin (pharmacology)
• Animals
• CD11c Antigen (metabolism)
• Caliciviridae Infections (complications, pathology, virology)
• Colony Count, Microbial
• Dendritic Cells (drug effects, metabolism)
• Drug Resistance, Bacterial (drug effects)
• Enterococcus (drug effects, growth & development)
• Gastroenteritis (complications, pathology, virology)
• Imidazoles (pharmacology)
• Interferon Type I (metabolism)
• Interleukin-1 (metabolism)
• Interleukin-23 (metabolism)
• Interleukins (metabolism)
• Ligands
• Mice, Inbred C57BL
• Norovirus (drug effects, physiology)
• Pancreatitis-Associated Proteins
• Proteins (metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptor 7 (metabolism)
• Vancomycin (pharmacology)
• Interleukin-22