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Recent:   

Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling

Lui et al., Virology, doi:10.1128/mbio.00392-24
Feb 2024  
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In Vitro study showing cyclosporine A (CsA) and the calcineurin-NFAT inhibitor VIVIT inhibit SARS-CoV-2 infection in lung epithelial Calu-3 cells. Authors find SARS-CoV-2 protein Nsp1 hijacks host NFAT signaling by binding calcineurin A, displacing regulator RCAN3 to drive NFAT activation. This induces DEAD-box helicase DDX5 to facilitate viral replication. Combining CsA or VIVIT with SARS-CoV-2 protease inhibitor nirmatrelvir shows synergistic antiviral effects. The results suggest targeting NFAT-DDX5 pathways may mitigate SARS-CoV-2 infection, while calcineurin inhibitors could enable protease inhibitor treatment for immunosuppressed patients.
Lui et al., 27 Feb 2024, peer-reviewed, 8 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMiscellaneousAll
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The immunosuppressant cyclosporine A (CsA) has ' 'been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained ' 'largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped ' 'CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression ' 'of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted ' 'with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 ' '(RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 ' 'replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin ' 'inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic ' 'antiviral effects when used in combination with nirmatrelvir. Our study delineated the ' 'molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the ' 'anti-SARS-CoV-2 action of calcineurin inhibitors.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>IMPORTANCE</jats:title>\n' ' <jats:p>Cyclosporine A (CsA), commonly used to inhibit immune responses, is also ' 'known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we ' 'provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: ' 'DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 ' 'controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral ' 'particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents ' 'suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in ' 'combination with Paxlovid.</jats:p>\n' ' </jats:sec>', 'DOI': '10.1128/mbio.00392-24', 'type': 'journal-article', 'created': {'date-parts': [[2024, 2, 27]], 'date-time': '2024-02-27T14:01:11Z', 'timestamp': 1709042471000}, 'update-policy': 'http://dx.doi.org/10.1128/asmj-crossmark-policy-page', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling', 'prefix': '10.1128', 'author': [ { 'given': 'Wai-Yin', 'family': 'Lui', 'sequence': 'first', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'given': 'Chon Phin', 'family': 'Ong', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'given': 'Pak-Hin Hinson', 'family': 'Cheung', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'given': 'Zi-Wei', 'family': 'Ye', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'given': 'Chi-Ping', 'family': 'Chan', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'ORCID': 'http://orcid.org/0000-0002-1921-5824', 'authenticated-orcid': True, 'given': 'Kelvin Kai-Wang', 'family': 'To', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Microbiology, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}, { 'given': 'Kit-San', 'family': 'Yuen', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}, {'name': 'School of Nursing, Tung Wah College, Kowloon, Hong Kong'}]}, { 'ORCID': 'http://orcid.org/0000-0002-2778-3530', 'authenticated-orcid': True, 'given': 'Dong-Yan', 'family': 'Jin', 'sequence': 'additional', 'affiliation': [ { 'name': 'School of Biomedical Sciences, The University of Hong Kong, ' 'Pokfulam, Hong Kong'}]}], 'member': '235', 'published-online': {'date-parts': [[2024, 2, 27]]}, 'reference': [ { 'key': 'e_1_3_4_2_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30154-9'}, {'key': 'e_1_3_4_3_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41591-022-01882-4'}, {'key': 'e_1_3_4_4_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abl8506'}, { 'key': 'e_1_3_4_5_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S1473-3099(22)00320-6'}, {'key': 'e_1_3_4_6_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj-2022-070695'}, {'key': 'e_1_3_4_7_2', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jmv.26140'}, { 'key': 'e_1_3_4_8_2', 'doi-asserted-by': 'publisher', 'DOI': 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