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

Abstract

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.

Norovirus Regulation by Host and Microbe

“…Acute MNoV strain MNV-1 stimulates greater type I and III IFN responses than persistent strain MNV.CR6, which may contribute to the development of enhanced adaptive immune responses and viral clearance [67]. However, a robust adaptive immune response alone is not sufficient for clearance of acute MNoV, as MNV-1 persists in mice lacking type I IFN signaling in DCs [62]. Extrapolating from MNoV findings, it is reasonable to assume that targeted IFN-related therapies might be potentially effective in HNoV clearance; however, the importance of differential adaptive immune responses to genetically diverse NoV strains may represent a challenge and will require further investigation.…”

Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine

“…These findings suggest a critical role for innate immunity and a less important role for adaptive immunity in control of persistent MNoV infection. In contrast, an acute strain of MNoV, CW3, which infects mice systemically and is cleared within 2 weeks in immunocompetent mice, is known to be controlled by type I and II interferons (Hwang et al, 2012; Maloney et al, 2012; Nice et al, 2016; Thackray et al, 2012) but a role for type III interferon in regulation of acute MNoV infection has not been reported. Both T-cell and B-cell responses are required to clear acute MNoV infection (Chachu et al, 2008a; Chachu et al, 2008b; Tomov et al, 2013).…”

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus

“…In fact, increased early viral replication in these mice leads to enhanced MNV-specific CTL and antibody responses, but this adaptive response fails to clear infection for at least 35 days. Mixed bone marrow chimeras indicate that the increased replication is due to cell intrinsic defects in CD11c-expressing cells (Figure 5) [93]. Although the specific cell type that harbors persistent virus in these mice is unknown, these data are consistent with MNV replication in CD11c-positive myeloid cells [59].…”

“…However, our recent work indicates that IFN-α/β plays a crucial role that is independent from B and T cell responses. CD11c-lineage-specific knockout of Ifnar1 , which includes MNV infected myeloid cells, enables systemic CW3 persistence without compromising B and T cell responses [93]. In fact, increased early viral replication in these mice leads to enhanced MNV-specific CTL and antibody responses, but this adaptive response fails to clear infection for at least 35 days.…”

“…C. Mice with a sub-population of myeloid cells deficient in IFNAR1 (LysM-cre × Ifnar1 f/f or CD11c-cre Ifnar1 f/f ) mount an enhanced CW3-specific T cell and B cell response. These cells remain functional, but are insufficient for clearance of viral infection [93]. …”