West Nile virus (WNV) is a neurotropic flavivirus that is the leading cause of arboviral encephalitis in the United States. The need to study WNV pathogenesis and the host immune response to infection is imperative as there are no specific therapies or vaccines available for human use. The search for effective intervention strategies relies on a better basic science understanding of the pathogenesis of WNV. Inflammatory monocytes are critical mediators of the antiviral response against WNV and accumulate in the CNS during WNV encephalitis. In preliminary data, we show that efficient accumulation of monocytes in the CNS first requires the release of monocyte from the bone marrow, a step that is entirely dependent on chemokine receptor CCR2. In this application, we will evaluate the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in mediating this monocytosis during WNV infection (Aim 1), and evaluate the extent to which these ligands, given exogenously, can promote monocyte accumulation in the CNS and alter the outcome of infection (Aim 2). Since monocytes appear to play a protective role within the CNS, understanding the chemokines that regulate their release from the bone marrow, and the potential to exploit this step to modulate monocyte accumulation in the CNS, is an important goal with translational implications.
This proposal seeks to understand how chemokines control WNV-induced monocytosis, which is required for efficient monocyte accumulation in the CNS and survival. Understanding the specific roles of the chemokines involved in this step will provide new insight into the fundamental biology of the host response to WNV and promote the development of more effective, targeted therapeutics.
|Michlmayr, Daniela; Bardina, Susana V; Rodriguez, Carlos A et al. (2016) Dual Function of Ccr5 during Langat Virus Encephalitis: Reduction in Neutrophil-Mediated Central Nervous System Inflammation and Increase in T Cell-Mediated Viral Clearance. J Immunol 196:4622-31|
|Hoffman, Kevin W; Sachs, David; Bardina, Susana V et al. (2016) Differences in Early Cytokine Production Are Associated With Development of a Greater Number of Symptoms Following West Nile Virus Infection. J Infect Dis 214:634-43|
|Bardina, Susana V; Michlmayr, Daniela; Hoffman, Kevin W et al. (2015) Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection. J Immunol 195:4306-18|