Multiple Mechanisms Contribute to Impairment of Type 1 Interferon Production during Chronic Lymphocytic Choriomeningitis Virus Infection of Mice

Abstract

Type 1 IFNs, innate cytokines with important effector and immunomodulatory properties, are rapidly induced in the acute phase of many virus infections; however, this is generally a transient response that is not sustained during virus persistence. To gain insight into mechanisms that can contribute to down-regulation of type 1 IFN production during virus persistence, we analyzed type 1 IFN production during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. High-level type 1 IFN production was transiently up-regulated in cells including plasmacytoid and conventional dendritic cells (DCs) following LCMV infection of mice, but LCMV persistence was associated with only low-level type 1 IFN production. Nonetheless, chronically infected mice were able to up-regulate type 1 IFN production in response to TLR3, 7, and 9 ligands, albeit less efficiently than uninfected mice. Splenic DC numbers in mice chronically infected with LCMV were decreased, and the remaining cells exhibited a reduced response to TLR stimulation. LCMV-infected cell lines efficiently up-regulated type 1 IFN production following TLR ligation and infection with a DNA virus, but exhibited a defect in type 1 IFN induction following infection with Sendai, an RNA virus. This block in type 1 IFN production by infected cells, together with abnormalities in DC numbers and functions, likely contribute to the low-level type 1 IFN production in mice chronically infected with LCMV. Impairment of type 1 IFN production may both promote virus persistence and impact on host immunocompetence. Understanding the mechanisms involved may assist in development of strategies for control of virus persistence and superinfection.

Induction and Inhibition of Type I Interferon Responses by Distinct Components of Lymphocytic Choriomeningitis Virus

“…Our previous studies have demonstrated that TLR2, TLR6, and CD14 are involved in LCMV-induced proinflammatory chemokines and cytokines (66). The mechanism by which LCMV induces type I IFN responses, however, has not been clearly defined (7,8,31,44). The role of the helicase family members RIG-I and MDA5 in virus-induced type I IFN responses has been recently established.…”

Inflammatory Monocytes Recruited to the Liver within 24 Hours after Virus-Induced Inflammation Resemble Kupffer Cells but Are Functionally Distinct

“…Since immunological studies of virusinduced hepatitis in human are difficult to perform (reviewed in references 8 and 9), infections of mice with lymphocytic choriomeningitis virus (LCMV) have demonstrated to be a valid model system to examine intrahepatic antiviral immunity (reviewed in reference 10). Although mice persistently infected with LCMV exhibit altered innate responses to subsequent Toll-like receptor (TLR) stimulations and secondary infections (11,12), the overall and intrahepatic alterations of the innate immune system during early LCMV infections have been less studied.Monocytes survey the body for inflammatory foci and are …”

Human Plasmacytoid Dendritic Cells Sense Lymphocytic Choriomeningitis Virus-Infected Cells In Vitro

“…Accordingly, HCV and LCMV have evolved mechanisms to block IFN induction in the infected cell (1,2). Nevertheless, HCV and LCMV infections strongly induce IFN and IFNstimulated gene (ISG) expression in vivo (3)(4)(5)(6)(7). Recently, we reported that Huh-7 cells infected with HCV or containing a subgenomic HCV replicon can trigger alpha/beta IFN (IFN-␣/␤) production in vitro by exosomal transfer of positive-strand HCV RNA to cocultured human peripheral blood-derived plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 7 (TLR7)-dependent manner without infecting them (1,8,9).…”

“…LCMV causes a longterm chronic infection in its natural host, the mouse. Human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious material (3)(4)(5)(6)(7)11). LCMV infection of humans can result in severe disease that in some cases can be fatal (12).…”