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.

Keywords: West Nile Virus; central nervous system; microglia; neuroinflammation.

Figure 1

Microglia phagocytic processes in WNV-infected CNS tissue. WNV-infected spinal cord slice cultures (SCSC) samples were collected at 6 days post infection (dpi) and processed for immunohistochemical staining with Iba1 (green) and WNV-E (red). (A) Fine filopodial projections directed toward WNV antigenic material are observed protruding from a lamellipodial projection of a microglia cell. Bar, 12 μm. (B) Microglial processes begin to engulf a WNV-infected cell, depicting the formation of a structure known as a phagocytic cup. Bar, 6 μm. (C) Microglia processes surround WNV antigenic material. Bar, 5 μm. (D) A microglia cell in the process of engulfing a WNV-infected cell. Bar, 9 μm. (E) Large lamellipodial processes from a single microglia cell surround a cluster of WNV-infected cells. Bar, 20 μm. (F) A WNV-infected cell is completely engulfed by a microglia cell, depicting the formation of a structure known as a phagosome. Bar, 8 μm. Quick et al. 2014 [41].

Figure 2

The many roles of microglia during a WNV infection. RECOGNITION OF VIRUS: Microglia recognize WNV viral particles in the CNS through multiple signaling pathways, including TLR3/MAVS [1,2]. MICROGLIAL RESPONSES AND RESOLUTION OF INFECTION: Microglia become activated in response to WNV infection and initiate morphological and functional changes [3]. Activated microglia control viral growth and reduce mortality in mice infected with WNV [4], likely due to a combination of microglial phagocytosis of infected neurons and the release of inflammatory cytokines, which contribute to neuroinflammation and the recruitment of lymphocytes [3,5]. In some cases, released cytokines may contribute to WNV-induced pathogenesis. MMP9 and ICAM-1 expression by microglia may enhance viral entry into the CNS through breakdown of the BBB and extravasation of potentially infected leukocytes [6,7]. LONG TERM EFFECTS: Following infiltration of T cells into the CNS, microglia may contribute to synaptic damage triggered by IFNγ produced by memory CD8⁺ T cells and enhanced by the complement cascade [8,9]. This synaptic elimination leads to neurological damage during recovery from WNV encephalitis [9]. Green and Red indicator arrows designate protective (green) and non-protective (red) microglial responses.