The Trans-omics Landscape of COVID-19 (preprint)

The outbreak of coronavirus disease 2019 (COVID-19) has been causing a global health emergency. Although previous studies investigated COVID-19 at different omics levels, the molecular hallmarks of COVID-19, especially in those patients without comorbidities, have not been fully investigated. Here, we presented a trans-omics landscape for COVID-19 based on integrative analysis of genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles from blood samples of 231 COVID-19 patients, ranging from asymptomatic to critically ill, importantly excluding those with any comorbidities. Notably, we found neutrophils heterogeneity existed between asymptomatic and critically ill patients. Expression discordance of inflammatory cytokines at mRNA and protein levels in asymptomatic patients could possibly be explained by post-transcriptional regulation by RNA binding proteins (RBPs) and microRNAs. Neutrophils over-activation, induced arginine depletion, and tryptophan metabolites accumulation contributed to T/NK cell dysfunction in critical patients. Anti-virus interferons were gradually suppressed along with disease severity. Overall, our study systematically revealed multi-omics characteristics of COVID-19, and the data we generated could hopefully help illuminate COVID-19 pathogenesis and provide valuable clues about potential therapeutic strategies for COVID-19.

The Trans-omics Landscape of COVID-19 (preprint)

System-wide molecular characteristics of COVID-19, especially in those patients without comorbidities, have not been fully investigated. We compared extensive molecular profiles of blood samples from 231 COVID-19 patients, ranging from asymptomatic to critically ill, importantly excluding those with any comorbidities. Amongst the major findings, asymptomatic patients were characterized by highly activated anti-virus interferon, T/natural killer (NK) cell activation, and transcriptional upregulation of inflammatory cytokine mRNAs. However, given very abundant RNA binding proteins (RBPs), these cytokine mRNAs could be effectively destabilized hence preserving normal cytokine levels. In contrast, in critically ill patients, cytokine storm due to RBPs inhibition and tryptophan metabolites accumulation contributed to T/NK cell dysfunction. A machine-learning model was constructed which accurately stratified the COVID-19 severities based on their multi-omics features. Overall, our analysis provides insights into COVID-19 pathogenesis and identifies targets for intervening in treatment.

Initial Study of Human Genetic Contribution to COVID-19 Severity and Susceptibility (preprint)

The COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third Peoples Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene locus associated with severity is located in TMEM189-UBE2V1 involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We also identified that the HLA-A*11:01, B*51:01 and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial study of Chinese patients provides a comprehensive view of the genetic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.