Abstract
Encephalitis resulting from viral infections is a major cause of hospitalization and death worldwide. West Nile Virus (WNV) is a substantial health concern as it is one of the leading causes of viral encephalitis in the United States today. WNV infiltrates the central nervous system (CNS), where it directly infects neurons and induces neuronal cell death, in part, via activation of caspase 3-mediated apoptosis. WNV infection also induces neuroinflammation characterized by activation of innate immune cells, including microglia and astrocytes, production of inflammatory cytokines, breakdown of the blood-brain barrier, and infiltration of peripheral leukocytes. Microglia are the resident immune cells of the brain and monitor the CNS for signs of injury or pathogens. Following infection with WNV, microglia exhibit a change in morphology consistent with activation and are associated with increased expression of proinflammatory cytokines. Recent research has focused on deciphering the role of microglia during WNV encephalitis. Microglia play a protective role during infections by limiting viral growth and reducing mortality in mice. However, it also appears that activated microglia are triggered by T cells to mediate synaptic elimination at late times during infection, which may contribute to long-term neurological deficits following a neuroinvasive WNV infection. This review will discuss the important role of microglia in the pathogenesis of a neuroinvasive WNV infection. Knowledge of the precise role of microglia during a WNV infection may lead to a greater ability to treat and manage WNV encephalitis.
Highlights
West Nile Virus (WNV) is a neurotropic, mosquito-borne, single-stranded RNA flavivirus maintained in an enzootic cycle between mosquitos, such as Culex pipiens, and perching birds, such as crows, jays, and finches [1,2]
Results in WNV-infected Plexxicon 5622 (PLX5622)-treated mice were remarkably similar to another recent study, which found that microglia are crucial for protection of mice from neurotropic coronavirus encephalitis and may be required for the generation of an efficient T cell response [49]
Elimination of microglia using PLX5622 between days 0 and 6 post-infection resulted in increased mortality in infected mice; microglial depletion after the first 6 days showed no effect on mortality [49]
Summary
West Nile Virus (WNV) is a neurotropic, mosquito-borne, single-stranded RNA flavivirus maintained in an enzootic cycle between mosquitos, such as Culex pipiens, and perching birds West Nile Virus viremia in humans is not high enough or sustained enough to support subsequent transmission to mosquitoes, humans are designated “dead-end” hosts [1,2]. West Nile Virus infection is the most common cause of epidemic viral encephalitis in the United States. About 80% of human WNV infections are asymptomatic and 20% of infections result in an acute illness, known as West Nile Fever, which is characterized by fever, headache, fatigue, anorexia, nausea, myalgia, and lymphadenopathy [2]. Less than 1% of human WNV infections lead to severe neurological disease including meningitis (inflammation of the membranes covering the brain and spinal cord), encephalitis (inflammation of the brain), or acute flaccid paralysis (rapid onset of weakness and loss of muscle tone) [2]. As there are currently no available human vaccines or antivirals targeting WNV, preventative methods such as the use of mosquito nets and control of mosquito populations are the predominant strategy for managing WNV infections in humans [1]
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