Neuroinflammation During RNA Viral Infections

Abstract

Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.

Keywords: RNA virus; blood-brain barrier; brain Trm; encephalitis; microglia; neuroinflammation; neurovascular unit.

Figure 1

CNS-resident and peripheral immune responses promote antiviral and immunopathogenic outcomes. Activation of CNS-resident neurons and glia, either directly by viral-sensing PRRs or indirectly, promotes antiviral and inflammatory cytokine expression and leads to restriction and resolution of viral infection. Prolonged glia activation additionally may initiate neuropathogenic programs. The innate immune response of CNS-resident cells also shapes the recruitment and activation of peripheral immune cells through the expression of chemokines, modulation of the BBB, and cell-cell interaction (not shown). Infiltration of immune cells is critical for viral clearance and establishment of long-term protection in the CNS, but it may facilitate neuroinvasion or contribute to neuropathology both during and after infection. Antiviral and immunopathogenic outcomes are labeled blue and red, respectively. Abbreviations: BBB, blood-brain barrier; BMEC, brain microvascular endothelial cell; CNS, central nervous system; PRR, pattern recognition receptor; Treg, regulatory T cell; Trm, tissue-resident memory T cell.