Molecular mechanisms of neuroinflammation and injury during acute viral encephalitis

Abstract

Viral infections in the central nervous system are a major cause of encephalitis. West Nile virus (WNV) and Herpes simplex virus (HSV) are the most common causes of viral encephalitis in the United States. We review the role of neuroinflammation in the pathogenesis of WNV and HSV infections in the central nervous system (CNS). We discuss the role of the innate and cell-mediated immune responses in peripheral control of viral infection, viral invasion of the CNS, and in inflammatory-mediated neuronal injury. By understanding the role of specific inflammatory responses to viral infections in the CNS, targeted therapeutic approaches can be developed to maximize control of acute viral infection while minimizing neuronal injury in the CNS.

Keywords: Encephalitis; Herpes simplex virus; Innate immunity; West Nile virus.

Fig. 1.

Average annual incidence of West Nile virus neuroinvasive disease reported to the CDC by county from 1999 to 2015. (Source: CDC ArboNet, Arboviral Diseases Branch.)

Fig. 2.

Mechanism of small flavivirus (sf) RNA production following host XRN1 degradation of flavivirus RNA. A) XRN1 mediated flavivirus RNA degradation halts in the 3′ untranslated region (UTR) at a conserved viral RNA stem loop structure. The remainder of the 3’UTR is processed to become sfRNA. B) Predicted RNA secondary structure of the flavivirus 3’UTR stem loops responsible for halting XRN1-mediated degradation. (Source: Chapman et al., eLife 2014; 3:e01892.)

Fig. 3.

Possible Mechanisms of WNV entry into the Central Nervous system. A) WNV and other related viruses may gain entry to the CNS following infection of olfactory neurons that have a single synapse that separates these neurons from the olfactory bulb in the CNS. B) WNV and other related viruses may also gain access to the CNS through the blood stream by direct infection of endothelial cells, break down of tight-junctions by MMP and TNFalpha, and/or by infecting infiltrating immune cells. MMP(matrix metalloproteinase), TNF (tumor necrosis factor). Adapted from Kristensson, 2011 and Cho & Diamond, 2012.

Fig. 4.

Possible mechanism of Herpes simplex virus type 1 entry into the CNS with subsequent spread to orbital-frontal and temporal lobes. A) HSV may gain entry via the olfactory nerves resulting in infection of the olfactory bulb and subsequent spread to adjacent temporal lobes (dashed arrow). HSV may also spread from the trigeminal ganglion to small sensory fibers that supply the basilar dura of the anterior and middle fossa (red arrows). B) Diagram of olfactory nerve synaptic pathways to the CNS. Olfactory rods of the receptor cells are directly exposed at the mucosal surface which synapses directly with mitral cells in the olfactory bulb in the CNS.