West Nile Virus (WNV) is an arthropod-borne virus that can cause neuroinvasive disease with significant long-term sequelae. The underlying CNS immunopathology results from the infiltration of inflammatory Ly6Chi monocytes into the brain. We have previously shown that treatment of WNV-infected mice with immune-modifying microparticles (IMP) on d6 p.i. results in the sequestration of Ly6Chi monocytes in the spleen, reducing their infiltration of the brain and increasing survival of WNV-infected mice by up to 70% while enabling protective immunity. To examine the impact of IMP treatment during early stage infection we used a skin model that mimics natural infection. In this model, infected WNV+ Mouse Embryonic Fibroblasts (MEF) were injected into the dermis of the ear and mice were treated with IMP at various time points, with the subsequent immune response in the ear and draining auricular lymph node (ALN) being examined using flow cytometric analysis. Our results indicate that on d1 p.i. Ly6Chi monocytes and plasmacytoid dendritic cells (pDC) populations in the ALN are significantly reduced in WNV+ MEF infected, IMP-treated mice compared to untreated WNV-infected mice. However, on d3 p.i. there were no significant differences between these immune cell subsets when comparing untreated and IMP-treated infected mice. Furthermore, there was a reduction in the number of T cells responding to infection in the ALN. We hypothesise that in this highly inflammatory model, the Ly6Chi monocytes and pDC may arise from a common precursor which is reduced by IMP-treatment, with both cells contributing to the inflammatory milieu that underpin the responses causing immunopathology. These findings highlight the necessity for further investigation of the relationship between Ly6Chi monocytes and pDC, and the importance of these cells early in the disease in WNV immune pathogenesis or protective antiviral responses.