West Nile virus (WNV) is a neuroinvasive flavivirus initiating an immunopathological response that causes lethal encephalitis. Recently, in a mouse model of intranasal WNV infection we showed intravenous immune-modifying microparticles (IMP) reduce CNS infiltration of Ly6Chi inflammatory monocytes by 50%, resulting in >60% survival in this lethal model. IMP+ inflammatory monocytes are sequestered by the spleen in the red pulp, with many IMP in marginal zone macrophages (MZM). Depletion of MZM with clodronate during WNV infection did not impair IMP efficacy. However, splenectomy abrogated the survival effect of IMP treatment. Importantly, splenectomised survivors showed long-term WNV immunity. Thus, by a yet undefined mechanism, the spleen, but not MZM, mediates the efficacy of IMP treatment in WNV encephalitis, but is not crucial for immunity, suggesting a role for secondary lymphoid organs in generating the adaptive immune response and contributing to immunopathology. Investigating leukocyte population dynamics in this model, we showed significant clonal expansion in the cervical lymph node, while the mesenteric and inguinal nodes had reduced T cell numbers. Our data suggest that T cells migrate to the cervical lymph nodes to contribute to the T cell effector populations generated in the adaptive immune response to CNS infection
