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A parsimonious approach for recognizing SARS‐CoV‐2 and host interactions

Abstract Effective countermeasures against the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) demand a better understanding of the pathogen‐host interactions. However, such information about the targets, responses, and effects in the host due to the virus is limited, especially so in the case of newly emerged pathogens. The peptide domains that form the interfaces of host and pathogen interacting proteins being evolutionarily conserved, it may be hypothesized that such interactions can be inferred from the similarities in the nucleotide sequences between the host and the pathogen. This communication reports the results of a study based on a parsimonious approach for the identification of the host‐virus interactions, where sequence complementarity between the human and SARS‐Cov‐2 genomes was used to predict several interactions between the host and SARS‐CoV‐2 at different levels of biological organization. In particular, the findings are suggestive of a direct effect of SARS‐CoV‐2 on cardiac health. The existing literature on host responses to SARS‐CoV‐2 and other viruses attest to many of these predicted interactions, supporting the utility of the proposed approach for the identification of host interactions with other novel pathogens.


| METHODS
All complete genome sequences of SARS-CoV-2 available as of March 25, 2020 at the Virus Pathogen Database and Analysis Resource (VIPR) 9 were added to the workbench and aligned using MUSCLE 10 with Unclust function at default settings. After completion of the multiple sequence alignment (MSA), the consensus sequence was generated using VIPR workbench analysis tools and gaps were removed. BioEdit 11 was used for visualization of the MSA and calculation of its entropy.
The consensus genome sequence of SARS-CoV-2 was used to query the human RefSeq Gene, genomic plus transcript (G + T), and PDB nucleotide databases, respectively, by blastn at default settings. 12 Irrespective of their expect values, all nonredundant hits from the blastn outputs were selected for further analysis; the hits from the human RefSeq Gene and transcript datasets were used to query STRING database 13 for network reconstruction and enrichment.

| RESULTS AND DISCUSSION
It was hypothesized that if a viral gene abc, coding for a protein ABC, was similar in sequence to a host gene xyz, coding for protein XYZ, then the viral protein ABC could possibly interact with some of the proteins in the host that the protein XYZ interacted with and thereby, compromise the functions and pathways served by XYZ.
Otherwise, the sequence similarity between abc and xyz could also possibly result in a gene silencing event in the host. Therefore, a consensus sequence of SARS-CoV-2 was derived and its local similarity to the human genome was investigated.  Sequence similarity with dentin sialophosphoprotein (dspp) gene as well as the involvement of enamel mineralization (GO:0070166) could be also inferred, hinting at the possibility of developmental defects in dentition and tooth decay in COVID-19 patients. The canine distemper virus, a member of Paramyxoviridae, is also known to interfere with enamel mineralization in its host, resulting in poor dentition in animals that suffer from the disease while their adult teeth are forming. 16 The involvement of two pathways viz. arrhythmogenic right ventricular cardiomyopathy (ARVC) (hsa05412) and glutamatergic synapse (hsa04724) was also identified ( Table 1). The enrichment of ARVC at the pathway level and of regulation of heart rate (GO:0002027), regulation of cardiac muscle contraction (GO:0055117), regulation of heart rate by cardiac conduction (GO:0086091), regulation of atrial cardiac muscle cell membrane repolarization (GO:0060372), and cardiac muscle cell action potential (GO:0086001) at the bioprocess level is highly suggestive of a direct cardiomyopathic effect of SARS-CoV-2; myocardial injury associated with in-hospital mortality has already been reported in confirmed and suspected COVID-19 patients. 17 Xiong et al. 14 have also reported the enrichment of ARVC-related transcriptional responses in COVID19 patients. It is important to note that cardiac comorbidities have been a major risk factor for COVID19related deaths 18 and that the penetrance of ARVC-related mutations is very high in the populations of the Mediterranean basin, especially Italy, 19 where the highest death rates due to this disease have been experienced.

CONFLICT OF INTERESTS
The author declares that there are no conflict of interests.

DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the supplementary material of this article.