West Nile virus encephalitis: sequential histopathological and immunological events in a murine model of infection

Abstract

West Nile virus (WNV) has emerged as an important cause of encephalitis in humans and horses in North America. Although there is significant knowledge about the pathogenesis of disease caused by this flavivirus and about the immunity against it, no reports exist describing the sequence of pathological changes and their correlation to the immune response in the brain following infection with WNV. In this report the authors describe the major histopathological changes, as well as changes in cytokine and chemokine expression, in brains from WNV-infected C57Bl/6 mice. During the course of infection skin, spleen and kidney were all sites of WNV replication before virus reached the brain. In brain, increased expression of the chemokines monocyte chemoattractant protein (MCP)-5 (CCL12), interferon gamma inducible protein 10 (IP-10; CXCL10), and monokine induced by gamma interferon (MIG; CXCL9) preceded the expression of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), which have previously been considered to be key early cytokines in the pathogenesis and immune response of WNV encephalitis. These results suggest that the chemokines MCP-5, IP-10, and MIG are important triggers of inflammation in brain due to their early up-regulation following WNV infection.

The role of chemokines in the pathogenesis of neurotropic flaviviruses

“…In mice, intradermal or subcutaneous WNV inoculation results in limited viral replication in the skin and draining lymph node [16][17][18]. Virus then reaches the blood stream and can access various peripheral organs, such as the spleen, and in some cases cross the BBB [18][19][20].…”

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…During the early phase of infection, arboviruses undergo an initial period of replication in the skin. Flaviviruses, such as WNV, replicate in both keratinocytes and skin dendritic cells (DCs), including Langerhans cells [102][103][104]. Infected DCs migrate to draining lymph nodes, leading to an additional round of infection and subsequent entry into the circulation via efferent lymphatic system and the thoracic duct.…”

Investigation of neuropathogenesis and control of an equine-pathogenic Australian West Nile virus isolate in an established CD1 Swiss white mouse and a novel rabbit model

“…As hypothesised from a later study, Garcia- Tapia [28]. Here, the recruited leucocytes could produce pro-inflammatory cytokines, such as TNFα and interleukins, which as mentioned above could compromise the BBB integrity [28,51]. Infected monocytes/macrophages and CD4 + lymphocytes could also facilitate productive viral replication in this region [68,70], providing a source of infection for brain microvascular endothelial cells, which in turn may exacerbate the BBB permeabilisation via the degradation of inter-endothelial tight junctions and upregulation of CAM expression [44,58].…”

“…Garcia-Tapia et al [68] suggested that WNV infected Langerhan cells migrated from the site of inoculation to draining lymph node, where infection could then be relayed to mononuclear cells, such as monocytes and certain subsets of CD4 + lymphocytes. As hypothesised from a later study, Garcia- Tapia [28]. Here, the recruited leucocytes could produce pro-inflammatory cytokines, such as TNFα and interleukins, which as mentioned above could compromise the BBB integrity [28,51].…”

“…According to current literature, viraemia develops following peripheral replication locally in the dermis at the site of virus inoculation [27][28][29] and/or in the draining lymph nodes [27,30,31], both resulting in systemic dissemination of the virus. Viral presence in the CNS is commonly observed shortly thereafter, especially in studies using immunocompromised rodents [31][32][33][34][35][36][37][38][39][40][41].…”