Abstract
The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in millions of deaths worldwide. The disease presents with various manifestations that can vary in severity and long-term outcomes. Previous efforts have contributed to the development of effective strategies for treatment and prevention by uncovering the mechanism of viral infection. We now know all the direct protein-protein interactions that occur during the lifecycle of SARS-CoV-2 infection, but it is critical to move beyond these known interactions to a comprehensive understanding of the "full interactome" of SARS-CoV-2 infection, which incorporates human microRNAs (miRNAs), additional human protein-coding genes, and exogenous microbes. Potentially, this will help in developing new drugs to treat COVID-19, differentiating the nuances of long COVID, and identifying histopathological signatures in SARS-CoV-2-infected organs. To construct the full interactome, we developed a statistical modeling approach called MLCrosstalk (multiple-layer crosstalk) based on latent Dirichlet allocation. MLCrosstalk integrates data from multiple sources, including microbes, human protein-coding genes, miRNAs, and human protein-protein interactions. It constructs "topics" that group SARS-CoV-2 with genes and microbes based on similar patterns of co-occurrence across patient samples. We use these topics to infer linkages between SARS-CoV-2 and protein-coding genes, miRNAs, and microbes. We then refine these initial linkages using network propagation to contextualize them within a larger framework of network and pathway structures. Using MLCrosstalk, we identified genes in the IL1-processing and VEGFA-VEGFR2 pathways that are linked to SARS-CoV-2. We also found that Rothia mucilaginosa and Prevotella melaninogenica are positively and negatively correlated with SARS-CoV-2 abundance, a finding corroborated by analysis of single-cell sequencing data.