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2.
Mbio ; 12(2):9, 2021.
Article in English | Web of Science | ID: covidwho-1434904

ABSTRACT

The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARSCoV-2 and emerging coronavirus animal model development. IMPORTANCE SARS-CoV-2 (the causative agent of COVID-19) is a major public health threat and one of two related coronaviruses that have caused epidemics in modern history. A method of screening potential infectible hosts for preemergent and future emergent coronaviruses would aid in mounting rapid response and intervention strategies during future emergence events. Here, we evaluated determinants of SARS-CoV-2 receptor interactions, identifying key changes that enable or prevent infection. The analysis detailed in this study will aid in the development of model systems to screen emergent coronaviruses as well as treatments to counteract infections.

3.
American Journal of Respiratory and Critical Care Medicine ; 203(9):1, 2021.
Article in English | Web of Science | ID: covidwho-1407045
4.
Wildlife trade, pandemics and the law: Fighting this year's virus with last year's law|2021. 94 pp. ; 2021.
Article in English | CAB Abstracts | ID: covidwho-1326688

ABSTRACT

This work describes the interactions between the trade in animals, regulations and the incidence of zoonoses, with emphasis on the current COVID-19 pandemic. The specific topics include the involvement of the World Health Organization, World Organization for Animal Health, CITES and other international organizations;national law assessments on animal health, animal welfare, animal quarantine, CITES implementing laws, customs, food safety, indigenous rights, meat industry, pet trade and wildlife conservation and trade;areas of concern;future opportunities and the next steps to be undertaken. This paper is the follow-up to a brief survey of legislation conducted by Legal Atlas in June 2020 regarding the existing legal approaches to controlling zoonotic disease risk in the context of wildlife trade.

5.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277737

ABSTRACT

Rationale: We have previously shown that particulate air pollution hampers antiviral responses to influenza virus in human nasal epithelial cells (hNECs) and that exposure to particulate matter from woodsmoke alters antiviral response to live attenuated influenza virus in the nasal epithelium. In 2020, more than 10 million acres of U.S. land burned in record-breaking wildfires and epidemiological data has indicated that increased exposure to particulate and gaseous air pollution is correlated with increased COVID-19 cases. Additionally, SARS-CoV-2 has demonstrated tropism for nasal epithelium more so than other airway regions. Hence, interactions between particulate air pollutants and antiviral responses in hNECs is likely regulating susceptibility to SARS-CoV-2 infections. Methods: Primary hNECs from 13 healthy donors (6 male, 7 female) were cultured at air liquid interface for six weeks, at which point ciliation and mucus production could be observed. Cells from 3 males and 3 females were exposed to particulate matter from diesel exhaust, woodsmoke from flaming eucalyptus, or woodsmoke from flaming red oak at 22 μg/cm2 for 2h. These cells were subsequently infected with SARS-CoV-2 and samples were collected at 0h, 24h, and 72h post infection for analysis of viral replication, expression of antiviral host defense markers, and biomarkers of inflammation. Results: Pilot data revealed that exposure of hNECs to 22 μg/cm2 of diesel exhaust particles for 2h decreased mRNA expression of genes related to antiviral responses, such as IRF1 and IRF3, DDX58, and CXCL10, but increased IL6 expression. However, hNEC exposure to diesel exhaust also decreased mRNA expression of ACE2 and TMPRSS2, two genes which provide crucial machinery for SARS-CoV-2 viral entry. Conclusions: Based on these pilot data we hypothesize that exposure to particulate air pollution from diesel exhaust and woodsmoke will increase viral load and severity of infection in hNECs infected with SARS-CoV-2. Ongoing analysis of viral replication, antiviral and inflammatory gene expression will further elucidate potential effects of different particulate air pollutants on SARS-CoV-2 infections.

6.
Topics in Antiviral Medicine ; 29(1):135-136, 2021.
Article in English | EMBASE | ID: covidwho-1250916

ABSTRACT

Background: We previously showed that β-D-N4-hydroxycytidine (rNHC) and its orally bioavailable prodrug, molnupiravir, acts as a broad-spectrum antiviral against coronaviruses in vitro and in vivo through lethal mutagenesis. Molnupiravir is currently in clinical trials for the treatment of SARS-CoV-2 infection. However, there are concerns that rNHC could be metabolized to dNHC and cause mutations in host cells. We examined the in vitro antiviral and mammalian cell mutagenic activity of three different nucleoside/base analogs, rNHC, favipiravir, and ribavirin, on SARS-CoV-2. We further examined the in vitro genotoxicity of a panel of antiviral nucleotide/nucleoside analogs, including rNHC, using a modified HPRT gene mutation assay. Methods: A549-hACE2 cells were infected with SARS-CoV-2 in the presence of nucleoside analogs. After 48 hours, the supernatants were collected and viral RNA was extracted. We constructed multiplexed-Primer ID libraries from viral RNA and sequenced them using MiSeq. HPRT knockout assays were performed using CHO-K1 cells treated with a panel of nucleotide/nucleoside analogs for 32 days. After 6-thioguanine selection, resistant cell colonies were counted as a measure of HPRT knockout mutations in host cells, and HPRT mRNA was sequenced from selected colonies. Results: rNHC showed dose-dependent antiviral and mutagenic effects against SAR-CoV-2 in vitro. In the 10 μM group, we found 7-fold and 14-fold increases in the overall substitution rate and the C to U mutation rate, respectively. The HPRT assay showed an rNHC dose-dependent increase in the number of resistant colonies with HPRT gene mutations. Other analogs showed no significant increase in the number of 6-thioG resistant colonies except for a slight increase with favipiravir (Fig 1a). Most colonies had missense substitutions or frame-shift deletions within HPRT mRNA, with most being distinct. Conclusion: rNHC showed a dose-dependent inhibition and mutagenic effect of SAR-CoV-2 in vitro. However, rNHC would be expected to be metabolized into the deoxynucleotide pool (by host RNR), resulting in DNA mutation of dividing mammalian cells. We demonstrated such mutagenic potential in a simple mammalian cell detection scheme. Molnupiravir has considerable potential as an orally bioavailable direct acting antiviral against SARS-CoV2 early in infection, especially in high risk patients. However, clinical use should be carefully considered in light of its potential mutagenic effects on the host.

8.
Journal of Immunology ; 204(1), 2020.
Article in English | EMBASE | ID: covidwho-881910

ABSTRACT

Immune homeostasis is the state where the immune system maintains stability in the absence of insult. Much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. There is evidence that homeostatic immunity can affect subsequent responses to infection or vaccination. Since the lungs are a major site of infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at the steady state. We found that all immune cell populations measured showed strong genetic (i.e. strain-specific) variation in cell type abundances. We identified 12 quantitative trait loci (QTL) associated with variation in 12 immune cell populations or the relationships between cell populations. Given the role of various immune cells in the lungs during respiratory virus pathogenesis, we asked whether any of the mapped QTL correlated with influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease following infection in the same strains of mice. Notably, a locus we mapped for baseline abundance of CD8+ T cells in the lungs was associated with peak weight loss following IAV infection. Additionally, a locus mapped for variation in Ly6C+ monocyte/macrophage abundance was associated with SARS-CoV titer at days 2 and 4 post-infection. These data suggest that abundance of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

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