Eastern equine encephalitis virus evades induction of the host immune response through miR-142-3p restriction of myeloid cell replication

Abstract

Abstract Eastern equine encephalitis virus (EEEV) is an alphavirus that causes the most virulent mosquito-borne disease in North America. We have previously determined that a myeloid cell-specific miRNA, miR-142-3p, binds to the 3′ non-translated region of EEEV suppressing virus replication and the induction of systemic IFN-α/β, promoting severe disease. Deletion of the miR-142-3p binding sites (virus 11337) rescues virus replication in myeloid cells, induces systemic IFN-α/β production, and leads to virus attenuation in vivo. We hypothesized that miR-142-3p restriction of EEEV replication in myeloid cells suppresses the adaptive immune response. Infection of C57BL6 mice with the myeloid tropic 11337 virus lead to increased cellularity in the popliteal lymph node (PLN) within 12 hours, predominantly comprised of CD11b+ F4/80+ Ly-6C+ inflammatory macrophages. Recruitment of inflammatory macrophages was significantly delayed in the non-myeloid tropic WT infected mice. NK cells and neutrophils were also recruited to the PLN after 11337 infection but not WT infection. In addition, 11337 infection of myeloid cells lead to increased cytokine and chemokine mRNA levels in the PLN compared to WT infection. In the spleen, 11337 infection lead to an increased frequency and number of epitope-specific CD8+ T cells compared to WT infection; however, the frequency was similar in the PLN. On day 6, epitope-specific CD8+ T cells expressed both KLRG1+ and CD127+during a WT infection while 11337 infection lead to the generation of short-lived effector cells (KLRG1+ CD127−). These results demonstrate that miR-142-3p restriction of EEEV replication in myeloid cells limits the induction of the host immune response and the generation of effector CD8+ T cells.