Theiler's virus strain-dependent induction of innate immune responses in RAW264.7 macrophages and its influence on viral clearance versus viral persistence

Abstract

Infection of susceptible mice with the DA strain of Theiler's murine encephalomyelitis virus (TMEV) induces a persistent central nervous system infection accompanied by demyelination that resembles multiple sclerosis. In contrast, Theiler's GDVII strain does not persist, because infected animals either clear the virus or die. Previously, the authors have shown that in vitro infection of RAW264.7 macrophages displays a similar strain-dependent outcome, resulting in the establishment of a persistent infection with the DA strain and clearance of the GDVII strain. Here, the authors show that when RAW264.7 cells were infected with both strains, the antiviral response triggered by the GDVII virus interfered with the DA virus' ability to induce a persistent infection. Treatment of cells with 2-aminopurine, a protein kinase R inhibitor, increased GDVII virus yields in contrast to DA virus yields. By comparing the antiviral activity of RAW264.7 macrophages against TMEV, it was found that GDVII-infected macrophages mounted a five times more potent antiviral response than the DA-infected ones, indicating that there are strain-dependent differences in the induction of host innate immune responses. Measurements of interferon (IFN) production confirmed this finding. In addition, it was found that the macrophages' antiviral response is dependent on the multiplicity of infection. The antiviral activity resulting from GDVII-infected macrophages could be partially neutralized with antibodies against IFN-alpha or IFN-gamma, but not with an anti-IFN-beta antibody. Because only a partial neutralization was reached, the authors speculate that apart from the investigated IFNs, other cellular factors contribute to the observed antiviral activity. Taken together, these results demonstrate the importance of host innate immune responses in determining the balance between viral clearance and viral persistence.