Osteopontin facilitates West Nile virus neuroinvasion via neutrophil “Trojan horse” transport

Abstract

West Nile virus (WNV) can cause severe human neurological diseases including encephalitis and meningitis. The mechanisms by which WNV enters the central nervous system (CNS) and host-factors that are involved in WNV neuroinvasion are not completely understood. The proinflammatory chemokine osteopontin (OPN) is induced in multiple neuroinflammatory diseases and is responsible for leukocyte recruitment to sites of its expression. In this study, we found that WNV infection induced OPN expression in both human and mouse cells. Interestingly, WNV-infected OPN deficient (Opn −/−) mice exhibited a higher survival rate (70%) than wild type (WT) control mice (30%), suggesting OPN plays a deleterious role in WNV infection. Despite comparable levels of viral load in circulating blood cells and peripheral organs in the two groups, WNV-infected polymorphonuclear neutrophil (PMN) infiltration and viral burden in brain of Opn −/− mice were significantly lower than in WT mice. Importantly, intracerebral administration of recombinant OPN into the brains of Opn −/− mice resulted in increased WNV-infected PMN infiltration and viral burden in the brain, which was coupled to increased mortality. The overall results suggest that OPN facilitates WNV neuroinvasion by recruiting WNV-infected PMNs into the brain.

Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications

“…In addition, clinical data also showed that PMNs were the predominant infiltrating leukocytes into the CNS of patients at the early stage of WNV neuroinvasive disease [145,146]. Our recent results show that WNV-infected neutrophils contribute to the viral burden in the mouse brain, suggesting neutrophils could play a major "Trojan horse" role in transporting WNV into the CNS [78]. However, it is possible that some of the neutrophils were infected after they arrived in the CNS.…”

“…Neutrophils can serve as reservoirs for WNV replication and dissemination in the early stages of infection but contribute to WNV clearance later in the infection process [77]. In addition, neutrophils have also been documented to facilitate WNV neuroinvasion via "Trojan horse" transport [78,79].…”

Research advancements in the neurological presentation of flaviviruses

“…Infection of microvascular pericytes in the brain can induce and/or amplify neuroinflammation caused by JEV infection . Researchers have found that the inflammatory chemokine osteopontin (OPN) can loosen the blood‐brain barrier in mice and promote WNV nerve invasive infection (Figure ) . The study found that interferon (IFN) signalling regulates permeability of the blood‐brain barrier after WNV infection .…”

“…There may be additional mechanisms that assist WNV infection of endothelial cells or the choroid plexus epithelium and passively transport the virus to the CNS. WNV infects olfactory nerves and spreads to olfactory bulbs, entering through a “Trojan horse mechanism.” Infected immune cells transport the virus to the CNS, and infected neurons are relayed to other neurons by retrograde transport …”

“…19 Researchers have found that the inflammatory chemokine osteopontin (OPN) can loosen the blood-brain barrier in mice and promote WNV nerve invasive infection (Figure 1). 20 The study found that interferon (IFN) signalling regulates permeability of the blood-brain barrier after WNV infection. 21 Some researchers have found that WNV affects the activation of the JAK-STAT pathway by reducing the steady-state level of tyrosine phosphorylation, antagonizing the immune response induced by IFN (Figure 1).…”