Neuron-intrinsic NF-κB Signaling Mediates Reovirus Virulence

Abstract

Pathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germline ablation of NF-κB subunit p50. It is not known whether the pro-apoptotic function of NF-κB is mediated by neuron-intrinsic processes, NF-κB-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-κB signaling in reovirus-induced neuronal injury, we established mice that lack NF-κB p65 expression in neurons using the Cre/loxP recombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural NF-κB p65 (Nsp65−/−) mice survived. While viral loads in brains of WT and Nsp65−/− were comparable, histological analysis revealed that reovirus antigen-positive areas in the brain of WT mice displayed enhanced cleaved caspase-3 immunoreactivity, a marker of apoptosis, compared with Nsp65−/− mice. These data suggest that neuron-intrinsic NF-κB-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected cortices of WT and Nsp65−/− mice suggests that NF-κB activation in neurons upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-κB-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations