A novel role for Osteopontin in facilitating West Nile virus neuroinvasion

Abstract

Abstract West Nile virus (WNV) is a positive sense, single-stranded RNA flavivirus that can cause human neuroinvasive diseases, including encephalitis and meningitis. The mechanisms by which WNV enters the central nervous system (CNS) and the host-factors that are involved in WNV neuroinvasion are not completely understood. In this study, we found increased production of soluble osteopontin (OPN) in human plasma following WNV infection compared to uninfected controls, indicating a role for OPN in WNV pathogenesis. In a mouse model, after challenge with WNV (2000 plaque forming units, PFU), OPN deficient (Opn−/−) mice exhibited a higher survival percentage (80%) than wild-type (WT) mice (20%). However, both groups had comparable levels of virus in circulating blood and peripheral organs. Interestingly, viral burden in the brains of Opn−/− mice were significantly lower than WT mice, which was coupled to reduced polymorphonuclear neutrophil (PMN) infiltration. Soluble OPN has been previously described as a chemokine for PMN recruitment, and intracerebral supplement of recombinant OPN (50 ng/mouse) followed by an intraperitoneal challenge of WNV (2000 PFU), resulted in increased PMN infiltration and WNV load within the CNS. Furthermore, we also confirmed that infected-PMNs carried WNV into the CNS. Together, these data suggest OPN plays a negative role in recruiting WNV-infected PMNs into the CNS, thus mediating WNV neuroinvasion.