The Role of Microglia during West Nile Virus Infection of the Central Nervous System

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.

Beneficial and detrimental functions of microglia during viral encephalitis

“…In a model of WNV infection, microglia have been shown to facilitate viral entry into the CNS. Deletion of the expression of matrix metalloproteinases (MMPs), more specifically MMP9, that are produced by microglia led to decreased viral loads within the CNS and increased survival of mice [84,85]. Previously, microglia have also been described to have a potential neurotoxic effect during viral infections, often but not exclusively in the context of crosstalk with other cell types in the brain (see following text).…”

Antiviral Cytokine Response in Neuroinvasive and Non-Neuroinvasive West Nile Virus Infection

“…The majority of the experimental data on the molecular mechanisms of WNV-induced neuropathogenesis are based on in vitro data and in vivo animal models showing that neurons, microglia and astrocytes represent the main cellular targets for infection in the CNS [ 9 ]. The hallmark of WNV neuroinvasive disease (WNND) pathogenesis is massive neuronal death attributed to caspase-3 and 9- mediated apoptosis involving both intrinsic and extrinsic pathways that is a result of both direct viral infection of neurons and indirect mechanisms mediated by cytotoxic factors such as proinflammatory cytokines [ 10 , 11 ]. The synthesis of neurotoxic factors and proinflammatory cytokines is mainly attributed to the WNV infection of microglia and recognition of a double stranded viral RNA intermediate in a TLR3-dependent manner [ 11 ].…”

“…The hallmark of WNV neuroinvasive disease (WNND) pathogenesis is massive neuronal death attributed to caspase-3 and 9- mediated apoptosis involving both intrinsic and extrinsic pathways that is a result of both direct viral infection of neurons and indirect mechanisms mediated by cytotoxic factors such as proinflammatory cytokines [ 10 , 11 ]. The synthesis of neurotoxic factors and proinflammatory cytokines is mainly attributed to the WNV infection of microglia and recognition of a double stranded viral RNA intermediate in a TLR3-dependent manner [ 11 ]. Infection of neurons also results in the synthesis of chemokines, including CCL9, CCL10 and CCL12, that enable the recruitment of WNV-specific T-cells expressing their corresponding receptors into the CNS [ 7 ].…”

Flavivirus Persistence in Wildlife Populations

“…Moreover, humoral and cell-mediated immune responses can be inhibited by arboviral flaviviruses [ 129 , 130 ]. For example, the assessment of WNV infection of hamsters (a genetic cousin of voles) has suggested WNV neutralizing antibody production may decrease the spread of this virus to the host’s central nervous system [ 131 , 132 , 133 ]. Conversely, WNV variant-mediated antibody evasion could result in the evasion of T-cell recognition [ 133 ], but a precise role in viral persistence has yet to be determined.…”