Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity

Longitudinal single cell atlas identifies complex temporal relationship between type I interferon response and COVID-19 severity

Nature Communications

10.1038/s41467-023-44524-0

http://dx.doi.org/10.1038/s41467-023-44524-0

Quy Xiao Xuan Lin, Deepa Rajagopalan, Akshamal M. Gamage, Le Min Tan, Prasanna Nori Venkatesh, Wharton O. Y. Chan, Dilip Kumar, Ragini Agrawal, Yao Chen, Siew-Wai Fong, Amit Singh, Louisa J. Sun, Seow-Yen Tan, Louis Yi Ann Chai, Jyoti Somani, Bernett Lee, Laurent Renia, Lisa F P Ng, Kollengode Ramanathan, Lin-Fa Wang, Barnaby Young, David Lye, Amit Singhal, Shyam Prabhakar

18 January 2024

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.-W., Singh, A., Sun, L. J., Tan, S.-Y., 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). https://doi.org/10.1038/s41467-023-44524-0

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.

Attribution 4.0 International (CC BY 4.0)

We are grateful to Nirmala Arul Rayan for initial guidance on single-cell and PBMC protocols and Shvetha Sankaran, Swaine Chen, and Muhammad Aminullah for setting up the BSL2+ lab, as well as Khor Chiea Chuen for assistance in genotyping.

This research / project is supported by the Agency for Science, Technology, and Research (A*STAR) - N/A
Grant Reference no. : CDAP201703-172-76-00056

This research / project is supported by the Agency for Science, Technology, and Research (A*STAR) - N/A
Grant Reference no. : IAF-PP-H18/01/a0/020

This research / project is supported by the Agency for Science, Technology, and Research (A*STAR) - N/A
Grant Reference no. : ACCL/19-GAP064-R20H-H

This research / project is supported by the National Medical Research Council - COVID-19 Research Fund
Grant Reference no. : COVID19RF-001

This research / project is supported by the National Medical Research Council - COVID-19 Research Fund
Grant Reference no. : COVID19RF-003

This research / project is supported by the National Medical Research Council - COVID-19 Research Fund
Grant Reference no. : COVID19RF-060

This research / project is supported by the National Medical Research Council - N/A
Grant Reference no. : OFLCG19May-0034

This research / project is supported by the Singapore National Research Foundation - N/A
Grant Reference no. : NRF2016NRF-NSFC002-013

This research / project is supported by the Singapore National Research Foundation - N/A
Grant Reference no. : NRF2018NRF-NSFC003SB-002

This research / project is supported by the Wellcome Trust/DBT India Alliance - IA/S/16/2/502700
Grant Reference no. : IA/S/16/2/502700

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https://oar.a-star.edu.sg/communities-collections/articles/20825

2041-1723

Infectious Disease Labs

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