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

Abstract

The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant 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 MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis 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-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19

“…Moreover, they found that haloperidol decreased viral replication in SARS-CoV-2-infected Vero E6 cells. In another more recent study, Gordon et al found in their analysis of a national electronic medical record database that fewer hospitalized COVID-19 patients who were newly prescribed haloperidol and other Sigma-binding typical antipsychotic medications progressed to requiring mechanical ventilation compared to those who were newly prescribed atypical antipsychotic medications that do not bind to Sigma receptors 14 .…”

SARS-CoV-2 infection remodels the host protein thermal stability landscape

“…IMPDH2 catalyses the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), which is a rate limiting step of de novo guanine biosynthesis. Inhibition of IMPDH2 with the antiviral ribavirin was previously shown to suppress SARS-CoV-2 replication 1 , as does its genetic ablation 6 . These results provide further evidence that IMPDH2 is functionally modi ed during infection, possibly by a direct interaction with nsp14, and provide more molecular insight into why IMPDH2 pharmacological inhibition effectively suppresses SARS-CoV-2 replication.…”

“…Consistent with a role for S604 in regulating SAFB function, the protein abundance of SAFB target genes FBL, RPS15 and TAF15 increased concomitantly with S604 levels ( Figure S4a). Notably, the SAFB target gene product LARP1 was previously found to interact with the SARS-CoV-2 N protein, and the target gene neuroguidin (NGDN) with the SARS-CoV-1 protein nsp9 3,6 . Con rming the functional relevance for SARS-CoV-2, NGDN was recently shown to be required for SARS-CoV-2 proliferation 25 .…”

“…Two days prior to infection, 1.5x10 6 Caco-2 cells were seeded in triplicate into plastic 10 cm tissue culture dishes (Greiner Cell State) per condition or in 8 well iBIDI chambers for IF staining. Caco-2 cells were infected with SARS-CoV-2 (BetaCoV/Germany/BavPat1/2020 p.1) at an MOI of 0.5 for 1 hour.…”

“…SARS-CoV-2 hijacks host protein cell processes for its replication, packaging, and release, leading to alterations in cell signaling and protein expression [1][2][3][4] . Although genetic approaches are shedding light onto the functional relevance of such large-scale proteomic information [5][6][7] , complementary approaches are needed to expand our understanding of the biophysical changes that proteins can undergo within a live infection context.…”