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Review
. 2021 Apr;53(4):483-494.
doi: 10.1038/s12276-021-00595-x. Epub 2021 Apr 7.

From bedside to bench: regulation of host factors in SARS-CoV-2 infection

Samantha Y Q Ong  1 , Ilya M Flyamer  2 , Wendy A Bickmore  2 , Simon C Biddie  3   4
Affiliations
Review

From bedside to bench: regulation of host factors in SARS-CoV-2 infection

Samantha Y Q Ong et al. Exp Mol Med. 2021 Apr.

Abstract

The zoonotic coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), which causes COVID-19 (coronavirus disease-2019), has resulted in a pandemic. This has led to an urgent need to understand the molecular determinants of SARS-CoV-2 infection, factors associated with COVID-19 heterogeneity and severity, and therapeutic options for these patients. In this review, we discuss the role of host factors in SARS-CoV-2 infection and describe variations in host factor expression as mechanisms underlying the symptoms and severity of COVID-19. We focus on two host factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), implicated in SARS-CoV-2 infection. We also discuss genetic variants associated with COVID-19 severity revealed in selected patients and based on genome-wide association studies (GWASs). Furthermore, we highlight important advances in cell and chromatin biology, such as single-cell RNA and chromatin sequencing and chromosomal conformation assays, as methods that may aid in the discovery of viral-host interactions in COVID-19. Understanding how regulation of host factor genes varies in physiological and pathological states might explain the heterogeneity observed in SARS-CoV-2 infection, help identify pathways for therapeutic development, and identify patients most likely to progress to severe COVID-19.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. ACE2 and TMPRSS2 mRNA human tissue expression.
Representation of RNA-seq-derived median protein-transcripts per million (pTPM) levels of ACE2 (a) and TMPRSS2 (b) genes in 54 nondiseased tissue sites in females (left) and males (right). Organs not labeled include the brain, aorta, coronary artery, heart, lungs, liver, esophagus, stomach, terminal ileum, colon (transverse, sigmoid), adrenal glands, kidney, and bladder. Data were obtained from Genotype-Tissue Expression (GTEx) Portal V8.
Fig. 2
Fig. 2. ACE2 and TMPRSS2 regulatory elements and tissue-invariant topologically-associated domains.
a Human tissue DNase-seq signals for ACE2 [left] and TMPRSS2 [right] loci. Tissue-specific regulatory elements (red bar) and shared regulatory elements (black bar) are highlighted. Datasets were obtained from the Encyclopedia of DNA Elements (ENCODE) 2018 data release for Hg38 and visualized via the UCSC genome browser. Normalized signal replicate pools are depicted for each tissue type. ENCODE experimental designations are ENCSR747YZZ (small intestine), ENCSR619JTC (lung), ENCSR955NXV (kidney), ENCSR871OSL (left ventricle) and ENCSR341MVE (brain). b Schematic representation of topologically-associated domains (TADs) showing boundaries for regulatory elements that control expression of the genes within a TAD. The formation of a TAD is dependent on insulator elements bound by CCCTC-binding factor (CTCF). Enhancer association with promoters via long-range interactions may act to regulate expression. Some enhancers harbor SNPs that might alter the expression pattern of genes within a TAD. c Hi-C data for human tissues depict chromosome conformation into TADs around ACE2 (left) and TMPRSS2 (right). The locations of the respective genes are indicated in black. Lung, right ventricle, small bowel, and cortex datasets were obtained from Schmitt et al.. Aorta data were obtained from Leung et al.. Hi-C datasets were visualized in HiGlass at 20-kb resolution. Datasets are aligned to human genome build Hg38. d Hi-C data for human lung fibroblast (IMR-90) and human endothelial (HUVEC) cell lines show higher-order chromosome organization as TADs. The genome locations of ACE2 (left) and TMPRSS2 (right) are indicated in black. Datasets aligned to human genome build Hg18 were obtained from Rao et al. and visualized in HiGlass at 8-kb resolution.
Fig. 3
Fig. 3. Single-nucleotide polymorphism (SNP) allelic frequencies of angiotensin-converting enzyme 2 (ACE2).
ACE2 (chromosome X: 15579156–15620271) exon coding transcripts are represented by boxes and corresponding shaded areas. Predicted loss-of-function (pLOF) and missense variants (top panel) and intron, splice region, 5’ untranslated region (UTR), and 3’UTR variants (bottom panel) are shown. The size of the dot reflects the minor allele count (range: 1-45,478), with minor allele frequency represented on the y-axis. Data were obtained from gnomAD v2.1.1.
Fig. 4
Fig. 4. The 3p21.31 locus harbors significant single-nucleotide variants from the COVID-19 GWAS.
The COVID-19 GWAS identified SNPs mapping to the 3p21.31 locus. The lead SNP from each study (rs11385942 from Ellinghaus et al.; rs73064425 from Pairo-Castineira et al.) mapped to LZTFL1. Images were generated from the UCSC genome browser (hg38, chr3:45,388,000–46,361,000), showing RefSeq genes and Genotype-Tissue Expression (GTEx) RNA-seq data for selected tissues.
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