RESUMEN
Neurological symptoms associated with COVID-19, acute and long term, suggest SARS-CoV-2 affects both the peripheral and central nervous systems (PNS/CNS). Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters, as well as primary peripheral sensory and autonomic neuronal cultures, show viral RNA, proteins, and infectious virus in PNS neurons, satellite glial cells, and functionally connected CNS tissues. Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.
Asunto(s)
COVID-19 , Neuropilina-1 , SARS-CoV-2 , Animales , SARS-CoV-2/fisiología , SARS-CoV-2/patogenicidad , COVID-19/virología , COVID-19/patología , COVID-19/metabolismo , Ratones , Neuropilina-1/metabolismo , Neuropilina-1/genética , Viremia/virología , Sistema Nervioso Central/virología , Sistema Nervioso Central/patología , Sistema Nervioso Central/metabolismo , Células Receptoras Sensoriales/virología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/patología , Mesocricetus , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Ratones Endogámicos C57BL , Internalización del Virus , MasculinoRESUMEN
The human betaherpesviruses, human cytomegalovirus (HCMV; species Human betaherpesvirus 5) and human herpesviruses 6A, 6B, and 7 (HHV-6A, -6B, and -7; species Human betaherpesviruses 6A, 6B, and 7) are highly prevalent and can cause severe disease in immune-compromised and immune-naive populations in well- and under-developed communities. Herpesvirus virion assembly is an intricate process that requires viral orchestration of host systems. In this review, we describe recent advances in some of the many cellular events relevant to assembly and egress of betaherpesvirus virions. These include modifications of host metabolic, immune, and autophagic/recycling systems. In addition, we discuss unique aspects of betaherpesvirus virion structure, virion assembly, and the cellular pathways employed during virion egress.