Dysregulation of Cell Signaling by SARS-CoV-2

Abstract

Pathogens usurp host pathways to generate a permissive environment for their propagation. The current spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection presents the urgent need to understand the complex pathogen-host interplay for effective control of the virus. SARS-CoV-2 reorganizes the host cytoskeleton for efficient cell entry and controls host transcriptional processes to support viral protein translation. The virus also dysregulates innate cellular defenses using various structural and nonstructural proteins. This results in substantial but delayed hyperinflammation alongside a weakened interferon (IFN) response. We provide an overview of SARS-CoV-2 and its uniquely aggressive life cycle and discuss the interactions of various viral proteins with host signaling pathways. We also address the functional changes in SARS-CoV-2 proteins, relative to SARS-CoV. Our comprehensive assessment of host signaling in SARS-CoV-2 pathogenesis provides some complex yet important strategic clues for the development of novel therapeutics against this rapidly emerging worldwide crisis.

Keywords: COVID-19; SARS-CoV-2; cell signaling; immune response; viral proteins.

Figure 1

Global Genomic Epidemiology of Novel Coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). (A) Phylogenetic analysis of 3485 genomes of SARS-CoV-2 sequences globally from December 2019 to December 2020. The different genetic variants of circulating SARS-CoV-2 are grouped into five clades defined by specific signature mutations showing their global distribution on the time scale. The clades 19A and 19B dominated the early outbreak in Wuhan and represent a higher proportion in Asia. Clades 20A, 20B, and 20C dominate in Europe and North America. (B) Geographical distribution of genomes. Each circle is centered on an individual country. The color indicates the region, and the size (area) of the circle represents the number of genomes from that country. (C) A ‘diversity’ panel that shows the novel coronavirus genome, its genes, and sites of amino acid mutations. (D) Subsection of subfigure (C) highlighting the mutation pattern in the 25 400–29 800 bp range of the genome. Apart from the spike (S) region, the genomic regions of open reading frame (ORF)14, ORF9b, ORF8, and ORF3a appear to be highly variable between clinical isolates of SARS-CoV-2. Source: latest global SARS-CoV-2 updated daily at https://nextstrain.org/sars-cov-2. Abbreviations: E, envelope; M, membrane.