The encephalitic response to
viral infection requires local
chemokine production and the ensuing recruitment of immune and inflammatory leukocytes. Accordingly,
chemokine receptors present themselves as plausible therapeutic targets for drugs aimed at limiting encephalitic responses. However, it remains unclear which
chemokines are central to this process and whether leukocyte recruitment is important for limiting viral proliferation and survival in the brain or whether it is predominantly a driver of coincident inflammatory pathogenesis. Here we examine
chemokine expression and leukocyte recruitment in the context of avirulent and virulent Semliki Forest virus (SFV) as well as
West Nile virus infection and demonstrate rapid and robust expression of a variety of inflammatory CC and
CXC chemokines in all models. On this basis, we define a
chemokine axis involved in leukocyte recruitment to the encephalitic brain during SFV
infection. CXCR3 is the most active; CCR2 is also active but less so, and CCR5 plays only a modest role in leukocyte recruitment. Importantly, inhibition of each of these receptors individually and the resulting suppression of leukocyte recruitment to the infected brain have no effect on viral titer or survival following
infection with a virulent SFV strain. In contrast, simultaneous blockade of CXCR3 and CCR2 results in significantly reduced mortality in response to virulent SFV
infection. In summary, therefore, our data provide an unprecedented level of insight into
chemokine orchestration of leukocyte recruitment in
viral encephalitis. Our data also highlight CXCR3 and CCR2 as possible therapeutic targets for limiting inflammatory damage in response to
viral infection of the brain.
IMPORTANCE:
Brain inflammation (
encephalitis) in response to
viral infection can lead to severe illness and even death. This therefore represents an important clinical problem and one that requires the development of new therapeutic approaches. Central to the pathogenesis of
encephalitis is the recruitment of inflammatory leukocytes to the infected brain, a process driven by members of the
chemokine family. Here we provide an in-depth analysis of the
chemokines involved in leukocyte recruitment to the virally infected brain and demonstrate that simultaneous blockade of two of these receptors, namely, CXCR3 and CCR2, does not alter viral titers within the brain but markedly reduces inflammatory leukocyte recruitment and enhances survival in a murine model of lethal
viral encephalitis. Our results therefore highlight
chemokine receptors as plausible therapeutic targets in treating
viral encephalitis.