Research Article: Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity

Date Published: June 21, 2016

Publisher: Public Library of Science

Author(s): Timothy J. Nice, Lisa C. Osborne, Vesselin T. Tomov, David Artis, E. John Wherry, Herbert W. Virgin, Carolyn B Coyne.


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.

Partial Text

The immune response to many commonly encountered viral infections results in viral clearance. Therefore, continuously replicating viral infections represent scenarios of an ineffective immune response or immune tolerance. Mechanistic studies of persistently replicating viral infections including lymphocytic choriomenengitis virus (LCMV) and murine hepatitis virus (MHV) mouse models have provided numerous insights into immune mechanisms of viral persistence [1–4]. In general, study of these and other models have focused on adaptive immune tolerance or the loss of adaptive immune function in determining viral persistence [5–8]. Thus, a paradigm has emerged that viral persistence is linked to defective or tolerant adaptive immune responses [3].

We have shown here that selective deficiency in the type I IFN response in DCs results in MNoV persistence. Prior studies utilizing the LCMV model causally link diminished CD8 T cell functionality to viral persistence [6] and other studies have demonstrate a role for type I IFN in regulating this process [25–29]. Furthermore, antigen abundance has been positively correlated with the degree of CD8 T cell dysfunction [5,30]. The MNoV persistence demonstrated herein contrasts with this paradigm as it was not associated with failure to generate an adaptive immune response or loss of adaptive immune function. In fact, there is an enhanced adaptive immune response commensurate with increased viral replication, and this enhanced adaptive immune response is sustained during persistent infection. These data demonstrate that an innate immune defect in type I IFN can result in viral persistence without attendant effects on the adaptive arm of the immune system. These results provide a different view of viral persistence than prior work in the LCMV model. However, it is important to note that antigen abundance may be lower in the MNoV model relative to the LCMV model. Additionally, the importance of type I IFN in protecting against lethal infection differs between CW3 and LCMV [17,25], providing a potential basis for differing roles of type I IFN in these two models.




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