Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

How lethal coronaviruses engage hosts Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely related to the deadly coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Considerable efforts are focused on developing treatments, and therapies that work across coronaviruses would be particularly valuable. Shedding light on the host factors hijacked by the viruses, Gordon et al. mapped the interactions between viral and human proteins for SARS-CoV-2, SARS-CoV-1, and MERS-CoV; analyzed the localization of viral proteins in human cells; and used genetic screening to identify host factors that either enhance or inhibit viral infection. For a subset of the interactions essential for the virus life cycle, the authors determined the cryo–electron microscopy structures and mined patient data to understand how targeting host factors may be relevant to clinical outcomes. Science, this issue p. eabe9403 Comparison of host interactions of three lethal coronaviruses identifies commonly hijacked pathways and potential drug targets. INTRODUCTION The emergence of three lethal coronaviruses in <20 years and the urgency of the COVID-19 pandemic have prompted efforts to develop new therapeutic strategies, including by repurposing existing agents. After performing a comparative analysis of the three pathogenic human coronaviruses severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), we identified shared biology and host-directed drug targets to prioritize therapeutics with potential for rapid deployment against current and future coronavirus outbreaks. RATIONALE Expanding on our recent SARS-CoV-2 interactome, we mapped the virus-host protein-protein interactions for SARS-CoV-1 and MERS-CoV and assessed the cellular localization of each viral protein across the three strains. We conducted two genetic screens of SARS-CoV-2 interactors to prioritize functionally-relevant host factors and structurally characterized one virus-host interaction. We then tested the clinical relevance of three more host factors by assessing risk in genetic cohorts or observing effectiveness of host factor–targeting drugs in real-world evidence. RESULTS Quantitative comparison of the 389 interactors of SARS-CoV-2, 366 of SARS-CoV-1, and 296 of MERS-CoV highlighted interactions with host processes that are conserved across all three viruses, including where nonorthologous proteins from different virus strains seem to fill similar roles. We also localized each individually-expressed viral protein by microscopy and then raised and validated antisera against 14 SARS-CoV-2 proteins to determine their localization during infection. On the basis of two independent genetic perturbation screens, we identified 73 host factors that, when depleted, caused significant changes in SARS-CoV-2 replication. From this list of potential drug targets, we validated the biological and clinical relevance of Tom70, IL17RA, PGES-2, and SigmaR1. A 3-Å cryo–electron microscopy structure of Tom70, a mitochondrial import receptor, in complex with SARS-CoV-2 ORF9b, provides insight into how ORF9b may modulate the host immune response. Using curated genome-wide association study data, we found that individuals with genotypes corresponding to higher soluble IL17RA levels in plasma are at decreased risk of COVID-19 hospitalization. To demonstrate the value of our data for drug repurposing, we identified SARS-CoV-2 patients who were prescribed drugs against prioritized targets and asked how they fared compared with carefully matched patients treated with clinically similar drugs that do not inhibit SARS-CoV-2. Both indomethacin, an inhibitor of host factor PGES-2, and typical antipsychotics, selected for their interaction with sigma receptors, showed effectiveness against COVID-19 compared with celecoxib and atypical antipsychotics, respectively. CONCLUSION By employing an integrative and collaborative approach, we identified conserved mechanisms across three pathogenic coronavirus strains and further investigated potential drug targets. This versatile approach is broadly applicable to other infectious agents and disease areas. Overview of the approaches taken for systemic and functional comparison of pathogenic human coronaviruses. (Left) Viral-human protein-protein interaction network mapping, viral protein localization studies, and functional genetic screens provide key insights into the shared and individual characteristics of each virus. (Right) Structural studies and hypothesis testing in clinical datasets demonstrate the utility of this approach for prioritizing therapeutic strategies. Nsp, nonstructural protein; ORF, open reading frame; ER, endoplasmic reticulum. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo–electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.