Innate immune response to SARS‐CoV‐2 infection contributes to neuronal damage in human iPSC‐derived peripheral neurons

Severe acute respiratory coronavirus 2 (SARS‐CoV‐2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS‐CoV‐2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell‐derived CNS and PNS neurons with SARS‐CoV‐2. SARS‐CoV‐2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS‐CoV‐2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN‐stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif‐containing protein 1, amyloid precursor protein and α‐synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS‐CoV‐2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019 (COVID‐19) related neuronal pathology and to test future preventive or therapeutic strategies.