tetano
Editor, Senior Moderator
J Med Virol
. 2024 Feb;96(2):e29455.
doi: 10.1002/jmv.29455. Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons
Vania Passos[SUP] 1 [/SUP], Lisa M Henkel[SUP] 2 [/SUP], Jiayi Wang[SUP] 1 [/SUP], Francisco J Zapatero-Belinchón[SUP] 3 4 5 [/SUP], Rebecca Möller[SUP] 3 [/SUP], Guorong Sun[SUP] 1 [/SUP], Inken Waltl[SUP] 6 [/SUP], Talia Schneider[SUP] 1 [/SUP], Amelie Wachs[SUP] 1 [/SUP], Birgit Ritter[SUP] 1 [/SUP], Kai A Kropp[SUP] 1 [/SUP], Shuyong Zhu[SUP] 1 [/SUP], Michela Deleidi[SUP] 7 8 [/SUP], Ulrich Kalinke[SUP] 4 6 [/SUP], Thomas F Schulz[SUP] 1 4 [/SUP], Günter Höglinger[SUP] 2 4 [/SUP], Gisa Gerold[SUP] 3 4 5 9 [/SUP], Florian Wegner[SUP] 2 [/SUP], Abel Viejo-Borbolla[SUP] 1 4 [/SUP]
Affiliations
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.
Keywords: JAK/STAT; SARM1; SARS-CoV-2; iPSC-derived peripheral neurons; interferon; neuronal damage.
. 2024 Feb;96(2):e29455.
doi: 10.1002/jmv.29455. Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons
Vania Passos[SUP] 1 [/SUP], Lisa M Henkel[SUP] 2 [/SUP], Jiayi Wang[SUP] 1 [/SUP], Francisco J Zapatero-Belinchón[SUP] 3 4 5 [/SUP], Rebecca Möller[SUP] 3 [/SUP], Guorong Sun[SUP] 1 [/SUP], Inken Waltl[SUP] 6 [/SUP], Talia Schneider[SUP] 1 [/SUP], Amelie Wachs[SUP] 1 [/SUP], Birgit Ritter[SUP] 1 [/SUP], Kai A Kropp[SUP] 1 [/SUP], Shuyong Zhu[SUP] 1 [/SUP], Michela Deleidi[SUP] 7 8 [/SUP], Ulrich Kalinke[SUP] 4 6 [/SUP], Thomas F Schulz[SUP] 1 4 [/SUP], Günter Höglinger[SUP] 2 4 [/SUP], Gisa Gerold[SUP] 3 4 5 9 [/SUP], Florian Wegner[SUP] 2 [/SUP], Abel Viejo-Borbolla[SUP] 1 4 [/SUP]
Affiliations
- PMID: 38323709
- DOI: 10.1002/jmv.29455
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.
Keywords: JAK/STAT; SARM1; SARS-CoV-2; iPSC-derived peripheral neurons; interferon; neuronal damage.