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Research Project: Intervention Strategies to Control Endemic and New and Emerging Viral Diseases of Swine

Location: Virus and Prion Research

Title: Integrate structural analysis, Isoform diversity, and interferon-inductive propensity of ACE2 to refine SARS-CoV2 susceptibility prediction in vertebrates

Author
item SANG, ERIC - TENNESSEE STATE UNIVERSITY
item TIAN, YUN - TENNESSEE STATE UNIVERSITY
item GONG, YUANYING - TENNESSEE STATE UNIVERSITY
item Miller, Laura
item SANG, YONGMING - TENNESSEE STATE UNIVERSITY

Submitted to: Heliyon
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/24/2020
Publication Date: 8/31/2020
Citation: Sang, E.R., Tian, Y., Gong, Y., Miller, L.C., Sang, Y. 2020. Integrate structural analysis, Isoform diversity, and interferon-inductive propensity of ACE2 to refine SARS-CoV2 susceptibility prediction in vertebrates. Heliyon. e04818. https://doi.org/10.1016/j.heliyon.2020.e04818.
DOI: https://doi.org/10.1016/j.heliyon.2020.e04818

Interpretive Summary: As a group of obligate pathogens, viruses need to enter a cell to replicate. Viral entry is a process that begins with attachment between a virus protein and a cell receptor(s) which allows for the virus to be internalized into the cell. Once inside the cell, the virus initiates replication starting the race between host immunity and a productive infection. For coronaviruses, the spike protein protruding from the viral surface is responsible for cell receptor binding and mediating viral entry. Several groups have reported that SARS-CoV2 uses the same angiotensin-converting enzyme 2 (ACE2) as the primary receptor for cell attachment similar to SARS-CoV discovered in 2003; however, SARS-CoV-2 has higher receptor affinity to human ACE2, which may ascribe to the efficacy of SARS-CoV2 infection in humans. For cross-species animal tropism, the potential infectivity of SARS-CoV2 in both wild and domestic animals, and potential for zoonotic transmission is a big public health concern. That concern involves two aspects: (1) screening to identify the animal species that serve as a virus reservoir originally passing SARS-CoV2 to humans; and (2) the existing risk of infected people to pass the virus to animals, particularly the domestic species, thus potentially forming an amplifying zoonotic cycle to worsen SARS-CoV2 evolution and prevalence. In this study, we evaluate cross-species ACE2 genetic (and especially epigenetic) diversity in regulation of ACE2 expression and functionality to determine the potential cell tropism and animal susceptibility to SARS-CoV2. When scoring the position of the promoter, a genetic segment that serves as a kind of "On" switch to initiate the biological process of transcription for the ACE2 gene, our data indicates that ACE2 transcription responds atypically to viral infection or the induction of interferons, a group of small proteins that play key roles in antiviral innate immunity, in a species-dependent manner.

Technical Abstract: The current new coronavirus disease (COVID-19) has caused globally near 0.4/6 million confirmed deaths/infected cases across more than 200 countries. As the etiological coronavirus (a.k.a. SARS-CoV2) may putatively have a bat origin, our understanding about its intermediate reservoir between bats and humans, especially its tropism in wild and domestic animals are mostly unknown. This constitutes major concerns in public health for the current pandemics and potential zoonosis. Previous reports using structural analysis of the viral spike protein (S) binding its cell receptor of angiotensin-converting enzyme 2 (ACE2), indicate a broad potential of SARS-CoV2 susceptibility in wild and particularly domestic animals. Through integration of key immunogenetic factors, including the existence of S-binding-void ACE2 isoforms and the disparity of ACE2 expression upon early innate immune response, we further refine the SARS-CoV2 susceptibility prediction to fit recent experimental validation. In addition to showing a broad susceptibility potential across mammalian species based on structural analysis, our results also reveal that domestic animals including dogs, pigs, cattle and goats may evolve ACE2-related immunogenetic diversity to restrict SARS-CoV2 infections. Thus, we propose that domestic animals may be unlikely to play a role as amplifying hosts unless the virus has further species-specific adaptation. Findings may relieve relevant public concerns regarding COVID-19-like risk in domestic animals, highlight virus-host coevolution, and evoke disease intervention through targeting ACE2 molecular diversity and interferon optimization.