Lymphocytic Choriomeningitis Virus Infection in FVB Mouse Produces Hemorrhagic Disease

Abstract

The viral family Arenaviridae includes a number of viruses that can cause hemorrhagic fever in humans. Arenavirus infection often involves multiple organs and can lead to capillary instability, impaired hemostasis, and death. Preclinical testing for development of antiviral or therapeutics is in part hampered due to a lack of an immunologically well-defined rodent model that exhibits similar acute hemorrhagic illness or sequelae compared to the human disease. We have identified the FVB mouse strain, which succumbs to a hemorrhagic fever-like illness when infected with lymphocytic choriomeningitis virus (LCMV). FVB mice infected with LCMV demonstrate high mortality associated with thrombocytopenia, hepatocellular and splenic necrosis, and cutaneous hemorrhage. Investigation of inflammatory mediators revealed increased IFN-γ, IL-6 and IL-17, along with increased chemokine production, at early times after LCMV infection, which suggests that a viral-induced host immune response is the cause of the pathology. Depletion of T cells at time of infection prevented mortality in all treated animals. Antisense-targeted reduction of IL-17 cytokine responsiveness provided significant protection from hemorrhagic pathology. F1 mice derived from FVB×C57BL/6 mating exhibit disease signs and mortality concomitant with the FVB challenged mice, extending this model to more widely available immunological tools. This report offers a novel animal model for arenavirus research and pre-clinical therapeutic testing.

IL‐33 promotes innate IFN‐γ production and modulates dendritic cell response in LCMV‐induced hepatitis in mice

“…This observation is consistent with a previous report, in which IL‐7‐induced IL‐17 did not result in myeloid cell activation, leading to liver or systematic injury . However, it was also reported that IL‐17 plays a pro‐inflammatory role in Ad infection or LCMV infection in Friend leukemia virus B strain (FVB) mice . The reason for the discrepancies may result from the different viral stocks and murine strains.…”

Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever

“…This suggested that T cell-driven systemic inflammation was essential for LASV pathogenesis, irrespective of viral loads. Analogous observation on T cell dependence of disease were subsequently also reported from two other surrogate models of AHF (Oestereich et al, 2016;Schnell et al, 2012), but the molecular mediators and pathways of AHF pathogenesis, which operate downstream of T cell activation, remain undefined.…”

“…Taken together, these observations indicated that the HHD model reproduced the differential susceptibility to LCMV-WE and LCMV-ARM as observed in guinea pigs and non-human primates (Lukashevich et al, 2002;Riviere et al, 1985). Three independent models of AHF have demonstrated T cell dependence of disease (Flatz et al, 2010b;Oestereich et al, 2016;Schnell et al, 2012). Hence, we first investigated whether HHD mice, devoid of murine MHC class I, mounted HLA-A2-restricted CD8 T cell responses to LCMV-WE infection.…”

Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes

“…For example, LCMV Cl-13 inoculation into certain strains of immunocompetent mice (C57Bl/6, Balb/CDJ, C3H, or SWR/J) lead to the persistent infection phenotype. In contrast, the same infection in NZB, SJL, or FVB/N mice induces death by 7 days post-challenge (Baccala et al, 2014; Schnell et al, 2012). The two distinct phenotypes are mediated by IFN-I but, in contrast, to the persistent infection, acute death is primarily due to IFN-α and not IFN-β (Baccala et al, 2014).…”