West Nile virus: immunity and pathogenesis

Abstract

West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that is maintained in an enzootic cycle between mosquitoes and birds, but can also infect and cause disease in horses and humans. WNV is endemic in parts of Africa, Europe, the Middle East, and Asia, and since 1999 has spread to North America, Mexico, South America, and the Caribbean. WNV infects the central nervous system (CNS) and can cause severe disease in a small minority of infected humans, mostly immunocompromised or the elderly. This review discusses some of the mechanisms by which the immune system can limit dissemination of WNV infection and elaborates on the mechanisms involved in pathogenesis. Reasons for susceptibility to WNV-associated neuroinvasive disease in less than 1% of cases remain unexplained, but one favored hypothesis is that the involvement of the CNS is associated with a weak immune response allowing robust WNV replication in the periphery and spread of the virus to the CNS.

Keywords: West Nile virus; central nervous system; neuroinvasion; pathogenesis.

Figure 1.

Frequency of infection of several regions of the human brain by West Nile virus. The areas most often infected by WNV include: the cerebral cortex, thalamus, basal ganglia, brainstem, cerebellum, and spinal cord (anterior horn) (indicated in dark red). Infection has less frequently been found in the olfactory bulb and hippocampus (indicated in orange).

Figure 2.

Regulation of Blood-brain barrier permeability, entry of WNV in the brain and factors involved in the pathogenesis of WNV-induced neuroinvasisve disease. Following inoculation of WNV in the dermis, virus infects and replicates in cells of the mononuclear lineage and neutrophils. Monocytes and neutrophils act as reservoirs for viral replication and dissemination, resulting in an increase in viral load. Recognition of WNV replication by TLR3 in monocytes leads to production of TNF-α and MMP-9 in a dose-dependent manner, resulting in loss of tight junctions, which allows entry of WNV and immune cells into the brain. High viral loads facilitate entry and dissemination of WNV into the brain. Expression of CXCL12 plays an important role in the retention of immune cells in the perivascular spaces of the CNS. Production of MMPs, cathepsins and plasmin by activated/infected monocytes and glial cells are probably involved in migration of cells from the perivascular space into the brain parenchyma. Furthermore, infected glial cells and neurons release neurotoxic mediators, leading to neuronal death. Neuronal death is mediated for a great part via the caspase-9 and caspase-3 pathway, which is dependent on the capsid of WNV. WNV: West Nile virus; TNF-α: Tumor necrosis factor-α; MMP: Matrix metalloproteinases; TLR: Toll-like receptor; CXCL: chemokine; IL: Interleukin; BBB: Blood-brain barrier; glial limitans: a network of foot processes of astrocytes.