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

Author: Jingjiao Li

Link to paper: https://www.biorxiv.org/content/10.1101/2020.03.31.019216v1.full.pdf+html

Journal/ Pre-Print: BioRxiv

Key Words: Proteomics, Interactome, neutrophils, cytokine storm

Research Highlights

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

Summary

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

Study Type

· In vitro study

· Clinical Cohort study (e.g. drug trials)

· Genome wide

· Proteomics

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).