title: Distinct Roles of Type I and Type III Interferons in Intestinal Immunity to Homologous and Heterologous Rotavirus Infections.
abstract: Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.|Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Jian-Da
authors.initials: JD
authors.lastname: Lin
authors.affiliation: Stanford University, Stanford, California, United States of America.|VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Ningguo
authors.initials: N
authors.lastname: Feng
authors.affiliation: Stanford University, Stanford, California, United States of America.|VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Adrish
authors.initials: A
authors.lastname: Sen
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Murugabaskar
authors.initials: M
authors.lastname: Balan
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Hsiang-Chi
authors.initials: HC
authors.lastname: Tseng
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Constance
authors.initials: C
authors.lastname: McElrath
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Smirnov
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Jianya
authors.initials: J
authors.lastname: Peng
authors.affiliation: Stanford University, Stanford, California, United States of America.|VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Yasukawa
authors.affiliation: Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Russell K
authors.initials: RK
authors.lastname: Durbin
authors.affiliation: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.|Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.|University Hospital Cancer Center, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Durbin
authors.affiliation: Stanford University, Stanford, California, United States of America.|VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Harry B
authors.initials: HB
authors.lastname: Greenberg
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.|Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.|University Hospital Cancer Center, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, Newark, New Jersey, United States of America.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007422:Intestines / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012401:Rotavirus; D012400:Rotavirus Infections / Q000276:immunology*
chemical_list: D007370:Interferon Type I; D007371:Interferon-gamma