Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity
Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age-...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/174907 |
| _version_ | 1811693051003797504 |
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| author | Lin, Quy Xiao Xuan Rajagopalan, Deepa Gamage, Akshamal M. Tan, Le Min Venkatesh, Prasanna Nori Chan, Wharton O. Y. Kumar, Dilip Agrawal, Ragini Chen, Yao Fong, Siew-Wai Singh, Amit Sun, Louisa J. Tan, Seow-Yen Chai, Louis Yi Ann Somani, Jyoti Lee, Bernett Renia, Laurent Ng, Lisa F. P. Ramanathan, Kollengode Wang, Lin-Fa Young, Barnaby Lye, David Singhal, Amit Prabhakar, Shyam |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Lin, Quy Xiao Xuan Rajagopalan, Deepa Gamage, Akshamal M. Tan, Le Min Venkatesh, Prasanna Nori Chan, Wharton O. Y. Kumar, Dilip Agrawal, Ragini Chen, Yao Fong, Siew-Wai Singh, Amit Sun, Louisa J. Tan, Seow-Yen Chai, Louis Yi Ann Somani, Jyoti Lee, Bernett Renia, Laurent Ng, Lisa F. P. Ramanathan, Kollengode Wang, Lin-Fa Young, Barnaby Lye, David Singhal, Amit Prabhakar, Shyam |
| author_sort | Lin, Quy Xiao Xuan |
| collection | NTU |
| description | Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy. |
| first_indexed | 2024-10-01T06:45:31Z |
| format | Journal Article |
| id | ntu-10356/174907 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:45:31Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1749072024-04-21T15:41:14Z Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity Lin, Quy Xiao Xuan Rajagopalan, Deepa Gamage, Akshamal M. Tan, Le Min Venkatesh, Prasanna Nori Chan, Wharton O. Y. Kumar, Dilip Agrawal, Ragini Chen, Yao Fong, Siew-Wai Singh, Amit Sun, Louisa J. Tan, Seow-Yen Chai, Louis Yi Ann Somani, Jyoti Lee, Bernett Renia, Laurent Ng, Lisa F. P. Ramanathan, Kollengode Wang, Lin-Fa Young, Barnaby Lye, David Singhal, Amit Prabhakar, Shyam Lee Kong Chian School of Medicine (LKCMedicine) Singapore Immunology Network, A*STAR A*STAR Infectious Diseases Labs Yong Loo Lin School of Medicine, NUS National Centre for Infectious diseases, Singapore Tan Tock Seng Hospital Medicine, Health and Life Sciences COVID-19 Disease severity Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This study was supported by the following grants: CDAP201703-172-76-00056, IAF-PP-H18/01/a0/020, and ACCL/19-GAP064-R20H-H from the Agency for Science, Technology, and Research (A*STAR), Singapore; COVID19RF-001, COVID19RF003, COVID19RF-060 and OFLCG19May-0034 from the Singapore National Medical Research Council COVID-19 Research Fund, NRF2016NRF-NSFC002-013, NRF2018NRF-NSFC003SB-002 from the Singapore National Research Foundation, and IA/S/16/2/502700 from the Wellcome Trust/DBT India Alliance. 2024-04-16T01:32:21Z 2024-04-16T01:32:21Z 2024 Journal Article Lin, Q. X. X., Rajagopalan, D., Gamage, A. M., Tan, L. M., Venkatesh, P. N., Chan, W. O. Y., Kumar, D., Agrawal, R., Chen, Y., Fong, S., Singh, A., Sun, L. J., Tan, S., Chai, L. Y. A., Somani, J., Lee, B., Renia, L., Ng, L. F. P., Ramanathan, K., ...Prabhakar, S. (2024). Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity. Nature Communications, 15(1), 567-. https://dx.doi.org/10.1038/s41467-023-44524-0 2041-1723 https://hdl.handle.net/10356/174907 10.1038/s41467-023-44524-0 38238298 2-s2.0-85182703262 1 15 567 en CDAP201703-172-76-00056 IAF-PP-H18/01/a0/020 ACCL/19-GAP064-R20H-H COVID19RF-001 COVID19RF003 COVID19RF-060 OFLCG19May-0034 NRF2016NRF-NSFC002-013 NRF2018NRF-NSFC003SB-002 Nature Communications © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences COVID-19 Disease severity Lin, Quy Xiao Xuan Rajagopalan, Deepa Gamage, Akshamal M. Tan, Le Min Venkatesh, Prasanna Nori Chan, Wharton O. Y. Kumar, Dilip Agrawal, Ragini Chen, Yao Fong, Siew-Wai Singh, Amit Sun, Louisa J. Tan, Seow-Yen Chai, Louis Yi Ann Somani, Jyoti Lee, Bernett Renia, Laurent Ng, Lisa F. P. Ramanathan, Kollengode Wang, Lin-Fa Young, Barnaby Lye, David Singhal, Amit Prabhakar, Shyam Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title | Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title_full | Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title_fullStr | Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title_full_unstemmed | Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title_short | Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity |
| title_sort | longitudinal single cell atlas identifies complex temporal relationship between type i interferon response and covid 19 severity |
| topic | Medicine, Health and Life Sciences COVID-19 Disease severity |
| url | https://hdl.handle.net/10356/174907 |
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