Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis
clinical drug discovery/repurposing proteomics
Author: Jingjiao Li
Journal/ Pre-Print: BioRxiv
Key Words: Proteomics, Interactome, neutrophils, cytokine storm
1. Elucidation of SARS-Cov-2 intra-viral and host-virus protein-protein interactions (PPI)
2. Proteomic profiling of PBMCs from COVID-19 patients with mild and severe disease
3. Identification of NKRF-nsp9 as a possible drug target and IL8/IL6 antagonists as drugs that could be repurposed for COVID19 treatment
The study investigates the viral-viral and viral-host protein interactome with genome-wide co-immunoprecipitation (in HEK293T) and yeast-two hybrid screens. Intra-viral PPI network suggest targets for small molecules or peptide drugs against specific epitopes. Host-viral PPI uncovered potential host targets, e.g. nsp9-NKRF facilitates IL-8/IL-6 production, possibly facilitating lung cytokine storm. The proteomic profile of PBMCs from COVID-19 patients examined and revealed an upregulation of innate immune responses (especially neutrophils) in mild cases compared to healthy controls and a functional decline in adaptive immunity in severe compared to mild cases. Only summary figures, not full results, were available at the time of writing.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Identification of new targets for treatment of SARS-CoV2/COVID19 positive individuals
· In vitro study
· Clinical Cohort study (e.g. drug trials)
· Genome wide
Strengths and limitations of the paper
Novelty: Proteomics of PBMCs from infected patients. NKRF as possible drug target. Intra-viral and host-virus full genome interactome
Standing in the field: It recapitulates data that indicate neutrophils are very abundant in initial COVID-19 followed by lymphopenia in more severe cases and reiterates that IL6 may be an important cytokine in the disease pathogenesis. It gives a possible explanation for excessive neutrophil infiltration in the lung and subsequent cytokine storm.
Appropriate statistics: yes where shown
Viral model used: SARS-CoV-2 Wuhan-Hu-1 isolate (for protein prediction)
Translatability: NKRF on patients as possible target to stop upregulation of IL-8/IL-6 and avoid excessive neutrophil migration into the lung and subsequent cytokine storm.
Main limitations: PPI studied in HEK293 cells (not the cells targeted by the virus). Different screening methods (Co-IP vs Y2H) give different results. Supplementary material not shown (only interactome map shown for most experiments). Small sample size for human PBMCs (surprisingly, the number of control PBMC samples is particularly low).