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

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 () and Shyam Prabhakar ()
Additional contact information
Quy Xiao Xuan Lin: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR)
Deepa Rajagopalan: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR)
Akshamal M. Gamage: Programme in Emerging Infectious Diseases, Duke-NUS Medical School
Le Min Tan: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR)
Prasanna Nori Venkatesh: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR)
Wharton O. Y. Chan: Programme in Emerging Infectious Diseases, Duke-NUS Medical School
Dilip Kumar: Singapore Immunology Network, A*STAR
Ragini Agrawal: Centre for Infectious Disease Research, Indian Institute of Science
Yao Chen: A*STAR Infectious Diseases Labs (A*STAR ID Labs), A*STAR
Siew-Wai Fong: A*STAR Infectious Diseases Labs (A*STAR ID Labs), A*STAR
Amit Singh: Centre for Infectious Disease Research, Indian Institute of Science
Louisa J. Sun: Alexandra Hospital
Seow-Yen Tan: Changi General Hospital
Louis Yi Ann Chai: National University Health System
Jyoti Somani: National University Health System
Bernett Lee: Singapore Immunology Network, A*STAR
Laurent Renia: A*STAR Infectious Diseases Labs (A*STAR ID Labs), A*STAR
Lisa F P Ng: A*STAR Infectious Diseases Labs (A*STAR ID Labs), A*STAR
Kollengode Ramanathan: National University of Singapore
Lin-Fa Wang: Programme in Emerging Infectious Diseases, Duke-NUS Medical School
Barnaby Young: Nanyang Technological University
David Lye: National University of Singapore
Amit Singhal: Singapore Immunology Network, A*STAR
Shyam Prabhakar: Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44524-0

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