Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points.

Nikki Bortell,Maria Cecilia G Marcondes,Howard S Fox,Claudia Flynn,Bruno Conti

doi:10.1155/2017/7582437

Nikki Bortell, Maria Cecilia G Marcondes + Show 3 more

Open Access

https://doi.org/10.1155/2017/7582437

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Abstract

Osteopontin (OPN) is a molecule that is common in central nervous system (CNS) pathologies, which participates in the activation, migration, and survival of inflammatory cells. However, the mechanisms by which OPN modulates inflammatory pathways are not clear. To understand the role of OPN in CNS viral infections, we used a lethal mouse model of West Nile virus (WNV), characterized by the injection of high doses of the Eg101 strain of WNV, causing the increase of OPN levels in the brain since early time points. To measure the impact of OPN in neuropathogenesis and resistance, we compared C57BI/6 WT with mice lacking the OPN gene (OPN KO). OPN KO presented a significantly higher mortality compared to WT mice, detectable since day 5 pi. Our data suggests that OPN expression at early time points may provide protection against viral spread in the CNS by negatively controlling the type I IFN-sensitive, caspase 1-dependent inflammasome, while promoting an alternative caspase 8-associated pathway, to control the apoptosis of infected cells during WNV infection in the CNS. Overall, we conclude that the expression of OPN maintains a critical threshold in the innate immune response that controls apoptosis and lethal viral spread in early CNS infection.

Highlights

The initial events following viral infection are crucial for pathogenesis and host outcome
We have found that osteopontin (OPN) is a proinflammatory molecule that is increased in the brain early after infection with West Nile virus (WNV), as well as in other central nervous system (CNS) pathologies, such as multiple sclerosis, experimental autoimmune encephalitis, experimental stroke, simian immunodeficiency virus (SIV), and Theiler’s virus infections [6,7,8,9,10,11]
The role of OPN in survival and viral entry was examined in wild-type (WT) and OPN knockout (OPN KO) mice by the intraperitoneal injection of a WNV Eg101 stock

Summary

Introduction

The initial events following viral infection are crucial for pathogenesis and host outcome. This is especially true for rapidly replicating viruses, such as West Nile virus (WNV), in the central nervous system (CNS), where cells such as neurons are not replenished. While the infection of neurons is quite efficient, several other cell types can host WNV replication. Two such cell types are macrophages and dendritic cells, which are likely responsible for the entry of the virus across the blood-brain barrier into the CNS [1, 2]

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