Virus-host interactome and proteomic survey of PBMCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis

Summary Background The ongoing coronavirus disease (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a global public health concern due to relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown. Methods Genome wide screening was used to establish intra-viral and viral-host interactomes. Quantitative proteomics was used to investigate peripheral blood mononuclear cell (PBMC) proteome signature in COVID-19. Findings We elucidated 286 host proteins targeted by SARS-CoV-2 and more than 350 host proteins that are significantly perturbed in COVID-19 derived PBMCs. This signature in severe COVID-19 PBMCs reveals significant upregulation of cellular proteins related to neutrophil activation and blood coagulation, as well as downregulation of proteins mediating T cell receptor signaling. From the interactome, we further identified that non-structural protein 10 interacts with NF-kappa-B-repressing factor (NKRF) to facilitate interleukin-8 (IL-8) induction, which potentially contributes to IL-8-mediated chemotaxis of neutrophils and the overexuberant host inflammatory response observed in COVID-19 patients. Conclusions Our study not only presents a systematic examination of SARS-CoV-2-induced perturbation of host targets and cellular networks but also reveals insights into the mechanisms by which SARS-CoV-2 triggers cytokine storms, representing a powerful resource in the pursuit for therapeutic intervention.