title: 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.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. abtm@mskcc.org pamere@mskcc.org.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Abt
authors.affiliation: Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Charlie G
authors.initials: CG
authors.lastname: Buffie
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Bože
authors.initials: B
authors.lastname: Sušac
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Becattini
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Carter
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Leiner
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Keith
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA.
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.affiliation: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. abtm@mskcc.org pamere@mskcc.org.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D017250:Caliciviridae Infections / Q000150:complications / Q000473:pathology / Q000821:virology; D015169:Colony Count, Microbial; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D016983:Enterococcus / Q000187:drug effects* / Q000254:growth & development*; D005759:Gastroenteritis / Q000150:complications / Q000473:pathology / Q000821:virology; D007093:Imidazoles / Q000494:pharmacology; D007370:Interferon Type I / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008024:Ligands; D008810:Mice, Inbred C57BL; D029322:Norovirus / Q000187:drug effects / Q000502:physiology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D014640:Vancomycin / Q000494:pharmacology*; D000097043:Interleukin-22
chemical_list: D000667:Ampicillin; D039521:CD11c Antigen; D007093:Imidazoles; D007370:Interferon Type I; D007375:Interleukin-1; D053759:Interleukin-23; D007378:Interleukins; D008024:Ligands; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D051199:Toll-Like Receptor 7; D014640:Vancomycin; D000097043:Interleukin-22; C490255:Reg3g protein, mouse; C402365:resiquimod