West Nile Virus spread and differential chemokine response in the central nervous system of mice: Role in pathogenic mechanisms of encephalitis

Abstract

Summary West Nile virus (WNV) is a zoonotic mosquito‐borne flavivirus able to cause severe neurological disease in humans, horses and various avian species. The more severe pathological changes of neurotropic WNV infection are caused by virus neuroinvasion and/or the immunological response in the central nervous system (CNS). The extent in which inflammatory cell trafficking orchestrated by chemokines is involved in the pathogenesis of CNS lesions has not been entirely elucidated. To understand the sequence of pro‐inflammatory chemokine induction during WNV encephalitis, a murine intranasal inoculation model was used. The relationship between lesional patterns in the mice CNS, the viral antigen distribution and the expression of pro‐inflammatory chemokine (CCL2, CCL5 and CXCL10) were evaluated. Viral antigen was first observed in olfactory tract and pyriform cortex neurons, suggesting a retrograde neuronal infection from the olfactory nerve. A spatio‐temporal association between WNV antigen and perivascular cuffs development was observed. Chemokine immunostaining was widely distributed in the brain from early stages. CCL2 immunolabelling was localised in neurons, astrocytes, microglia and endothelial cells as well as mononuclear leucocytes within perivascular cuffs. In contrast, CCL5 and CXCL10 immunostaining were mainly observed in astroglia and neurons, respectively. A strong correlation was demonstrated between the presence of perivascular cuffs and CCL2 and CCL5 expression in most brain areas, while CXCL10 was only associated with inflammatory lesions in few specific regions. Importantly, a strong correlation between WNV and CCL5 distribution was observed. However, no correlation was observed between CXCL10 and viral antigen. Neurons were confirmed as the main target cells of WNV, as well as one of the sources of CCL2, CCL5 and CXCL10. This study shows the sequence and comparative distribution pattern between histological lesions, WNV antigen and chemokine expression over the infection process. Furthermore, it identifies potential targets for immune intervention to suppress damaging chemokine responses.

IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

“…Interestingly, loss of IFN-I signaling resulted in further elevated expression of CCL5 (probably as a compensatory mechanism). Studies conducted with WNV virus infection also shows that increase in cytokine and chemokine response to be part of CNS pathogenesis [26]. IFN-I-independent expression of CXCL-10 in the case of HIV-I infection is shown previously, and our study is in-line with these observations [40].…”

“…Similarly, in another alphavirus, Sindbis virus infection, the Interferon-gamma (IFN-γ) modulates resolution of CNS inflammation by promoting tissue-resident CD8 memory T (T RM ) response while restricting peripheral T cell entry [25]. In a similar line, West Nile fever virus (WNV) infection in a mouse model showed overexpression of proinflammatory chemokines such as CCL2, CCL5, and CXCL10, collectively modulating the immunopathology in the brain [26]. Other than IFN-I, various factors determine the quality of CNS immune response.…”

New Insights into the Susceptibility of Immunocompetent Mice to Usutu Virus

“…Primary means of USUV entry to the brain are still to be determined. The pattern of WNV spread into the CNS may include both hematogenous or neuronal routes [46] and vary according to the route of inoculation [47]. In Vero cells, USUV can establish a persistent infection for at least 80 days [48].…”

“…This hypothesis is reinforced by the results of Vielle et al [49], which showed that human respiratory epithelial cells of the nasal cavity are targets for USUV replication in vitro. Intranasal infection of immunocompetent mice with certain WNV strains resulted in fatal encephalitis and death of the animal [47,[50][51][52], and in avian models, bird to bird transmission of WNV was experimentally confirmed [53]. A histopathological study including sections from the nasal cavity epithelium and the CNS (notably the olfactory bulb) at different stages of the infection would be needed to discern lesional patterns compatible with USUV replication in vivo.…”

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

“…Evidence that microglia are activated during WNV-induced CNS disease in humans includes the presence of microglial nodules and increased proliferation [ 51 , 52 ]. Activated microglia are also seen in the CNS of mice infected with WNV [ 53 , 54 , 55 ] and in WNV-infected ex vivo brain and spinal cord slice cultures [ 21 , 41 ]. The use of ex vivo slice cultures allows for isolation of the CNS immune system from the peripheral immune response.…”