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.

WNV infections of the CNS are rare but can have devastating long-term effects. There are currently no vaccines or specific antiviral treatments, so a better understanding of the pathogenesis and immune response to this virus is crucial.

Although rare, WNV encephalitis poses a devastating health concern, with few treatment options and frequent long-term neurological sequelae. Currently, there are no human vaccines or specific antivirals against WNV infections, so further research into potential new therapeutic agents is critical.

Background: Characteristic features/biomarkers of innate immune system activation and inflammation are associated with neurodegenerative diseases (e.g., Alzheimer's disease [AD], Parkinson's disease [PD]), Down syndrome [DS], normal aging, and many infectious diseases. Evidence also suggests that peripheral inflammation interacts with and mirrors inflammation in the central nervous system (CNS) and can yield useful biomarkers of the disease or disorder and potentially of the efficacy of therapies. These findings have led to the additional conclusion that developing methods to dampen inflammation would be an effective therapeutic approach. However, recent findings indicate that innate immune system activation, including inflammation, may, instead, be beneficial. Method:We used the proinflammatory cytokine granulocyte-macrophage colonystimulating factor (GM-CSF) to modulate the innate immune system and determine the effects on biomarker, clinical, and/or behavioral outcomes in mouse models of AD, DS, aging, and viral infection and in a clinical trial in AD.Result: Recent published and unpublished results from our laboratory and others show that treatment with GM-CSF increases inflammatory biomarkers and also effectively reduces cognitive decline, brain pathology, and disease-associated peripheral blood biomarkers in mouse models of AD, PD, DS, and normal aging. Interestingly, GM-CSF treatment also reduces viral titer and mortality in mouse models of West Nile Virus and SARS-CoV-2 infection. Our retrospective study of patients with cognitive deficits due to chemotherapy-induced CNS inflammation showed that recombinant human GM-CSF (sargramostim) treatment was associated with improved cognition. A sargramostim clinical trial in PD also showed promising results. Finally, our recentlycompleted clinical trial in AD showed that sargramostim treatment increased inflammatory cytokines and improved toward normal both a measure of cognition (MMSE) and blood biomarkers of amyloid (A) and Tau (T) deposition and neurodegeneration (N).Sargramostim clinical trials in COVID-19 are underway.