Infection, transport and degeneration of human neurons caused by severe acute respiratory syndrome coronavirus 2

• Applicant: Professor Dr. Abel Viejo-Borbolla
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Virology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458632757

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19). SARS-CoV-2 has caused a pandemic infecting millions of people with hundreds of thousands of deaths. Many infected individuals have symptoms associated with neuronal infection, including loss of taste, of smell, acute cerebrovascular disease, encephalopathy, seizure and lack of unconscious breathing. Moreover, infection of neurons is linked with the severity of disease, high morbidity and mortality. The use of human neurons derived from stem cells is providing relevant information on the neurotropism of SARS-CoV-2. SARS-CoV-2 productively infects neurons from the central nervous system (CNS) in vitro, leading to efficient virus production and spread (4, 5). However, there is no information on the infection of neurons from the peripheral nervous system (PNS) despite some of the observed symptoms in COVID-19 patients (e.g., loss of smell, taste, lack of unconscious breathing) point to this as an important pathomechanism. Therefore, in this project we will study the infection of human peripheral neurons by SARS-CoV-2. The main objectives of this proposal are:(i) To investigate SARS-CoV-2 replication and transport in human peripheral neurons.(ii) To determine the pathogenicity of SARS-CoV-2 infection of peripheral neurons.Peripheral neurons are highly polarized, with very long neurites. Infection of peripheral neurons could take place through the hematogenous route or through neurite transport. We will investigate the outcome of infection at the cell body and at the neurite end and determine whether SARS-CoV-2 is transported in an anterograde or retrograde manner. This is important because retrograde transport will allow invasion of peripheral ganglia from the innervated organs, such as the lungs. Furthermore, anterograde transport may carry the virus from peripheral neurons into the CNS, causing life-threatening diseases such as encephalopathy.Viral infection might lead to neurodegeneration and neuronal death. This can be observed at the cell bodies or at the neurites. Moreover, neurite degeneration plays a role in the intrinsic immune response of the neurons to reduce virus spread. We will investigate whether SARS-CoV-2 infection of human peripheral neurons results in neurodegeneration and cell death. Our results will, for the first time, provide information on the infection and transport of SARS-CoV-2 in peripheral neurons. They will also address the pathomechanisms of SARS-CoV-2 infection of human neurons. This will facilitate the development of novel therapeutic strategies to avoid neurological complications during COVID-19.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Stephanie Pfänder