Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.
In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon, United States of America.
Timothy J
TJ
Nice
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Lisa C
LC
Osborne
Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
Vesselin T
VT
Tomov
Department of Microbiology and Immunology, and Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America.
David
D
Artis
Department of Microbiology, and Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
E John
EJ
Wherry
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Herbert W
HW
Virgin
D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D017250:Caliciviridae Infections / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029322:Norovirus; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000276:immunology*; D014779:Virus Replication / Q000502:physiology
D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta