Abstract
Newly emerged SARS-CoV-2 is the cause of an ongoing global pandemic leading to severe respiratory disease in humans. SARS-CoV-2 targets epithelial cells in the respiratory tract and lungs, which can lead to amplified chloride secretion and increased leak across epithelial barriers, contributing to severe pneumonia and consolidation of the lungs as seen in many COVID-19 patients. There is an urgent need for a better understanding of the molecular aspects that contribute to SARS-CoV-2-induced pathogenesis and for the development of approaches to mitigate these damaging pathologies. The multifunctional SARS-CoV-2 Envelope (E) protein contributes to virus assembly/egress, and as a membrane protein, also possesses viroporin channel properties that may contribute to epithelial barrier damage, pathogenesis, and disease severity. The extreme C-terminal (ECT) sequence of E also contains a putative PDZ-domain binding motif (PBM), similar to that identified in the E protein of SARS-CoV-1. Here, we screened an array of GST-PDZ domain fusion proteins using either a biotin-labeled WT or mutant ECT peptide from the SARS-CoV-2 E protein. Notably, we identified a singular specific interaction between the WT E peptide and the second PDZ domain of human Zona Occludens-1 (ZO1), one of the key regulators of TJ formation/integrity in all epithelial tissues. We used homogenous time resolve fluorescence (HTRF) as a second complementary approach to further validate this novel modular E-ZO1 interaction. We postulate that SARS-CoV-2 E interacts with ZO1 in infected epithelial cells, and this interaction may contribute, in part, to tight junction damage and epithelial barrier compromise in these cell layers leading to enhanced virus spread and severe dysfunction that leads to morbidity. Prophylactic/therapeutic intervention targeting this virus-host interaction may effectively reduce airway and/or gastrointestinal barrier damage and mitigate virus spread.
Highlights
Members of the Coronaviridae family are enveloped with a positive-sense single-stranded RNA genome and helical nucleocapsid [1, 2]
We postulate that SARS-CoV-2 E interacts with Zona Occludens-1 (ZO1) in infected epithelial cells, and this interaction may contribute, in part, to tight junction damage and epithelial barrier compromise in these cell layers leading to enhanced virus spread and severe dysfunction that leads to morbidity
Since the DLLV core motif is perfectly conserved in the SARS-CoV-2 E protein (Wuhan-Hu-1 strain), and the immediately adjacent amino acids, not identical, are highly conserved with those of SARS-CoV-1 E (Fig 1), the likelihood that SARS-CoV-2 E protein can interact with select PDZ-domains of host proteins is high [13, 21, 28, 29, 31, 38]
Summary
Members of the Coronaviridae family are enveloped with a positive-sense single-stranded RNA genome and helical nucleocapsid [1, 2]. A highly pathogenic human coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-1), emerged in 2003 to cause acute respiratory disease in afflicted individuals [6,7,8,9]. In December 2019, SARS-coronavirus 2 (SARS-CoV-2) emerged as the etiological agent of severe respiratory disease, called Coronavirus Disease 2019 (COVID-19), first identified in patients in Wuhan, Hubei province, China. This initial outbreak has become a global pandemic and has afflicted over 128 million people and claimed over 2.8 million lives worldwide as of March 2021 [10,11,12,13,14]. It is imperative to investigate how this novel SARS-CoV-2 interacts with the host to cause such severe disease pathology
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