Coxsackievirus is a common viral pathogen in newborn infants that is capable of causing pancreatitis, myocarditis, and meningitis in the acute stages of infection. Due to the ability of the virus to target the brain, a neonatal mouse model was developed in order to study the effects of coxsackievirus B3 (CVB3) in the central nervous system (CNS). A novel population of myeloid cells was observed that rapidly entered the neonatal CNS through the choroid plexus, which mediates the blood-cerebral spinal fluid barrier, specifically after CVB3 infection. These myeloid cells were highly susceptible to infection, based on the expression of eGFP from recombinant eGFP expressing coxsackievirus (eGFP-CVB3). They were also found to express nestin, a neural stem cell marker, and move from the choroid plexus into the parenchyma of the brain, as observed by serial immunofluorescence images. Therefore, these cells may provide an innovative method of viral dissemination in the neonatal CNS. In addition, a unique chemokine induction profile was detected in the choroid plexus following CVB3 infection which may contribute to myeloid cell infiltration and subsequent choroid plexus damage. These results with CVB3 were then compared to lymphocytic choriomeningitis virus (LCMV), a contrasting neurotropic RNA virus in the neonatal CNS, and several differences in stem cell tropism, the immune response and pathology were found. The neonatal mouse model also revealed that neural progenitor and stem cells (NPSCs) are highly susceptible to CVB3 infection. Since severalpicornaviruses have recently been shown to induce autophagy in order to aid viral replication, we investigated the role of autophagy during acute CVB3 infection in NPSCs. We revealed that CVB3 infection in NPSCs does not induce autophagy, in contrast to cardiomyocytes. Thus, we hypothesize that the role of autophagy during CVB3 infection is cell-type specific. Taken together, these results show that acute CVB3 infection in the neonatal CNS elicits a unique and multifaceted response from the host.