Temporal dynamics of the host molecular responses underlying severe COVID-19 progression and disease resolution

EBioMedicine

Sarah H Ooi¹  Shirin Kalimuddin²  Wen Chong Chia³  Summer L Zhang³  Hwee Cheng Tan³  Eng Eong Ooi³  Jenny G Low³  Clara WT Koh³  Kuan Rong Chan⁴  Eugenia Z Ong⁴ 

[1] Department of Infectious Diseases, Singapore General Hospital, 169608 Singapore;Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857 Singapore;Program in Emerging Infectious Diseases, Duke-NUS Medical School, 169857 Singapore;Viral Research and Experimental Medicine Center, SingHealth Duke-NUS Academic Medical Centre (ViREMiCS), 169856 Singapore;

关键词: SARS-CoV-2;    COVID-19 recovery;    COVID-19 pathogenesis;    Transcriptome profiling;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: The coronavirus disease-19 (COVID-19) pandemic has cost lives and economic hardships globally. Various studies have found a number of different factors, such as hyperinflammation and exhausted/suppressed T cell responses to the etiological SARS coronavirus-2 (SARS-CoV-2), being associated with severe COVID-19. However, sieving the causative from associative factors of respiratory dysfunction has remained rudimentary. Methods: We postulated that the host responses causative of respiratory dysfunction would track most closely with disease progression and resolution and thus be differentiated from other factors that are statistically associated with but not causative of severe COVID-19. To track the temporal dynamics of the host responses involved, we examined the changes in gene expression in whole blood of 6 severe and 4 non-severe COVID-19 patients across 15 different timepoints spanning the nadir of respiratory function. Findings: We found that neutrophil activation but not type I interferon signaling transcripts tracked most closely with disease progression and resolution. Moreover, transcripts encoding for protein phosphorylation, particularly the serine-threonine kinases, many of which have known T cell proliferation and activation functions, were increased after and may thus contribute to the upswing of respiratory function. Notably, these associative genes were targeted by dexamethasone, but not methylprednisolone, which is consistent with efficacy outcomes in clinical trials. Interpretation: Our findings suggest neutrophil activation as a critical factor of respiratory dysfunction in COVID-19. Drugs that target this pathway could be potentially repurposed for the treatment of severe COVID-19. Funding: This study was sponsored in part by a generous gift from The Hour Glass. EEO and JGL are funded by the National Medical Research Council of Singapore, through the Clinician Scientist Awards awarded by the National Research Foundation of Singapore.

【 授权许可】

Unknown