Axonal Transport Enables Neuron-to-Neuron propagation of HCoV-OC43.

Human coronaviruses (HCoV) are recognized respiratory pathogens for which accumulating evidence indicates that in vulnerable patients, the infection can cause more severe pathologies. HCoVs are not always confined to the upper respiratory tract and can invade the CNS upon still unclear circumstances. HCoV-induced neuropathologies in human are difficult to diagnose early enough to allow therapeutic interventions. Making use of our already described animal model of HCoV neuropathogenesis, we describe the route of neuropropagation from the nasal cavity to the olfactory bulb, piriform cortex then brainstem. We identified neuron-to-neuron propagation as one underlying mode of virus spreading in cell culture. Our data demonstrate that both passive diffusion of released viral particles and axonal transport are valid propagation strategies used by the virus. We describe for the first time the presence along axons of viral platforms whose static dynamism are reminiscent of viral assembly sites. We further revealed that HCoV-OC43 modes of propagation could be modulated by selected HCoV-OC43 proteins and axonal transport. Our work, therefore, identifies processes that may govern the severity and nature of HCoV-OC43 neuropathogenesis and will make possible the development of therapeutic strategies to prevent occurrences. IMPORTANCE Coronaviruses may invade the CNS, disseminate and participate in the induction of neurological diseases. Their neuropathogenicity is being increasingly recognized in humans, and the presence and persistence of human coronaviruses (HCoV) in human brains was proposed to cause long-term sequelae. Using our mouse model relying on natural susceptibility to HCoV-OC43 and neuronal cell cultures, we have defined the most relevant path taken by HCoV-OC43 to access and spread to and within the CNS toward the brainstem and spinal cord and studied in cell culture the underlying modes of intercellular propagation to better understand its neuropathogenesis. Our data suggest that the axonal transport governs HCoV-OC43 egress in the CNS leading to exacerbate neuropathogenesis. Exploiting knowledge on neuroinvasion and dissemination will enhance our ability to control viral infection within the CNS as it will shed light on underlying mechanisms of neuropathogenesis and uncover potential "druggable" molecular virus-host interfaces.