Introduction: COVID-19 typically causes Q7 respiratory disorders, but a high proportion of patients also reports neurological and neuromuscular symptoms during and after SARSCoV-2 infection. Despite a number of studies documenting SARS-CoV-2 infection of various neuronal cell populations, the impact of SARS-CoV-2 exposure on motor neuronal cells specifically has not been investigated so far. Methods: Thus, by using human iPSC-derived motor neurons (iPSC-MNs) we assessed: (i) the expression of SARS-CoV-2 main receptors; (ii) iPSC-MN infectability by SARS-CoV-2; and (iii) the effect of SARS-CoV-2 exposure on iPSC-MN transcriptome. Results: Gene expression profiling and immunofluorescence (IF) analysis of the main host cell receptors recognized by SARS-CoV-2 revealed that all of them are expressed in iPSC-MNs, with CD147 and NRP1 being the most represented ones. By analyzing SARS-CoV-2 N1 and N2 gene expression over time, we observed that human iPSC-MNs were productively infected by SARS-CoV-2 in the absence of cytopathic effect. Supernatants collected from SARS-CoV-2-infected iPSC-MNs were able to re-infect VeroE6 cells. Image analyses of SARS-CoV-2 nucleocapsid proteins by IF confirmed iPSC-MN infectability. Furthermore, SARS-CoV-2 infection in iPSCMNs significantly altered the expression of genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated with cell survival and metabolism, as well as antiviral and inflammatory response. Discussion: These results suggest for the very first time that SARS-CoV-2 can productively infect human iPSC-derived MNs probably by binding CD147 and NRP1 receptors. Such information will be important to unveil the biological bases of neuromuscular disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms.

Human motor neurons derived from induced pluripotent stem cells are susceptible to SARS-CoV-2 infection / G. Cappelletti, C. Colombrita, F. Limanaqi, S. Invernizzi, M. Garziano, C. Vanetti, C. Moscheni, S. Santangelo, S. Zecchini, D. Trabattoni, V. Silani, M. Clerici, A. Ratti, M. Biasin. - In: FRONTIERS IN CELLULAR NEUROSCIENCE. - ISSN 1662-5102. - 17:(2023), pp. 1285836.1-1285836.12. [10.3389/fncel.2023.1285836]

Human motor neurons derived from induced pluripotent stem cells are susceptible to SARS-CoV-2 infection

G. Cappelletti
Primo
;
C. Colombrita
Secondo
;
F. Limanaqi;S. Invernizzi;M. Garziano;C. Vanetti;C. Moscheni;S. Santangelo;S. Zecchini;D. Trabattoni;V. Silani;M. Clerici;A. Ratti
Co-ultimo
;
M. Biasin
Co-ultimo
2023

Abstract

Introduction: COVID-19 typically causes Q7 respiratory disorders, but a high proportion of patients also reports neurological and neuromuscular symptoms during and after SARSCoV-2 infection. Despite a number of studies documenting SARS-CoV-2 infection of various neuronal cell populations, the impact of SARS-CoV-2 exposure on motor neuronal cells specifically has not been investigated so far. Methods: Thus, by using human iPSC-derived motor neurons (iPSC-MNs) we assessed: (i) the expression of SARS-CoV-2 main receptors; (ii) iPSC-MN infectability by SARS-CoV-2; and (iii) the effect of SARS-CoV-2 exposure on iPSC-MN transcriptome. Results: Gene expression profiling and immunofluorescence (IF) analysis of the main host cell receptors recognized by SARS-CoV-2 revealed that all of them are expressed in iPSC-MNs, with CD147 and NRP1 being the most represented ones. By analyzing SARS-CoV-2 N1 and N2 gene expression over time, we observed that human iPSC-MNs were productively infected by SARS-CoV-2 in the absence of cytopathic effect. Supernatants collected from SARS-CoV-2-infected iPSC-MNs were able to re-infect VeroE6 cells. Image analyses of SARS-CoV-2 nucleocapsid proteins by IF confirmed iPSC-MN infectability. Furthermore, SARS-CoV-2 infection in iPSCMNs significantly altered the expression of genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated with cell survival and metabolism, as well as antiviral and inflammatory response. Discussion: These results suggest for the very first time that SARS-CoV-2 can productively infect human iPSC-derived MNs probably by binding CD147 and NRP1 receptors. Such information will be important to unveil the biological bases of neuromuscular disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms.
SARS-CoV-2 infection; iPSC-derived motor neurons; long-COVID; neuroinflammation; neuromuscular disorders; COVID-19
Settore BIO/13 - Biologia Applicata
   One Health Basic and Translational Research Actions addressing Unmet Need on Emerging Infectious Diseases (INF-ACT)
   INF-ACT
   MINISTERO DELL'UNIVERSITA' E DELLA RICERCA
   PE00000007
2023
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1019909
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