PHEV infection: A promising model of betacoronavirus-associated neurological and olfactory dysfunction

Abstract

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus belonging to the genus Betacoronavirus. Similar to pathogenic coronaviruses to which humans are susceptible, such as SARS-CoV-2, PHEV is transmitted primarily through respiratory droplets and close contact, entering the central nervous system (CNS) from the peripheral nerves at the site of initial infection. However, the neuroinvasion route of PHEV are poorly understood. Here, we found that BALB/c mice are susceptible to intranasal PHEV infection and showed distinct neurological manifestations. The behavioral study and histopathological examination revealed that PHEV attacks neurons in the CNS and causes significant smell and taste dysfunction in mice. By tracking neuroinvasion, we identified that PHEV invades the CNS via the olfactory nerve and trigeminal nerve located in the nasal cavity, and olfactory sensory neurons (OSNs) were susceptible to viral infection. Immunofluorescence staining and ultrastructural observations revealed that viral materials traveling along axons, suggesting axonal transport may engage in rapid viral transmission in the CNS. Moreover, viral replication in the olfactory system and CNS is associated with inflammatory and immune responses, tissue disorganization and dysfunction. Overall, we proposed that PHEV may serve as a potential prototype for elucidating the pathogenesis of coronavirus-associated neurological complications and olfactory and taste disorders. PHEV, a neurotropic porcine betacoronavirus (β-CoV), primarily infects and replicates in the respiratory tract and CNS in suckling pigs. Neurological complications and anosmia (i.e., inability to perceive odor or loss of olfactory function) are common clinical features in coronavirus-induced diseases, however the underlying mechanisms remain unclear. In this study, we investigated the pathogenesis of neurological and olfactory dysfunction in a murine model of PHEV infection. The data underscore that PHEV invades the CNS via the olfactory and trigeminal nerves, and that anosmia and neurological manifestations are associated with direct OSNs infection and neuroimmune inflammation. The utilization of PHEV prototype will provide a platform for future studies on the neuroinvasion and neuropathogenesis of human pathogenic coronaviruses.