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1.
Emerg Microbes Infect ; 9(1): 1567-1579, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-622041

ABSTRACT

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).


Subject(s)
Betacoronavirus/physiology , Chiroptera/virology , Membrane Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , RNA-Binding Proteins/metabolism , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Animals , Betacoronavirus/classification , HEK293 Cells , Humans , Rats , SARS Virus/physiology , Viverridae
2.
Prog Biophys Mol Biol ; 155: 29-35, 2020 09.
Article in English | MEDLINE | ID: covidwho-611000

ABSTRACT

In December 2019, an atypical pneumonia invaded the city of Wuhan, China, and the causative agent of this disease turned out to be a new coronavirus. In January 2020, the World Health Organization named the new coronavirus 2019-nCoV and subsequently it is referred to as SARS-CoV2 and the related disease as CoViD-19 (Lai et al., 2020). Very quickly, the epidemic led to a pandemic and it is now a worldwide emergency requiring the creation of new antiviral therapies and a related vaccine. The purpose of this article is to review and investigate further the molecular mechanism by which the SARS-CoV2 virus infection proceeds via the formation of a hetero-trimer between its protein S, the ACE2 receptor and the B0AT1 protein, which is the "entry receptor" for the infection process involving membrane fusion (Li et al., 2003). A reverse engineering process uses the formalism of the Hill function to represent the functions related to the dynamics of the biochemical interactions of the viral infection process. Then, using a logical evaluation of viral density that measures the rate at which the cells are hijacked by the virus (and they provide a place for the virus to replicate) and considering the "time delay" given by the interaction between cell and virus, the expected duration of the incubation period is predicted. The conclusion is that the density of the virus varies from the "exposure time" to the "interaction time" (virus-cells). This model can be used both to evaluate the infectious condition and to analyze the incubation period. BACKGROUND: The ongoing threat of the new coronavirus SARS-CoV2 pandemic is alarming and strategies for combating infection are highly desired. This RNA virus belongs to the ß-coronavirus genus and is similar in some features to SARS-CoV. Currently, no vaccine or approved medical treatment is available. The complex dynamics of the rapid spread of this virus can be demonstrated with the aid of a computational framework. METHODS: A mathematical model based on the principles of cell-virus interaction is developed in this manuscript. The amino acid sequence of S proein and its interaction with the ACE-2 protein is mimicked with the aid of Hill function. The mathematical model with delay is solved with the aid of numerical solvers and the parametric values are obtained with the help of MCMC algorithm. RESULTS: A delay differential equation model is developed to demonstrate the dynamics of target cells, infected cells and the SARS-CoV2. The important parameters and coefficients are demonstrated with the aid of numerical computations. The resulting thresholds and forecasting may prove to be useful tools for future experimental studies and control strategies. CONCLUSIONS: From the analysis, I is concluded that control strategy via delay is a promising technique and the role of Hill function formalism in control strategies can be better interpreted in an inexpensive manner with the aid of a theoretical framework.


Subject(s)
Betacoronavirus/metabolism , Cell Membrane/metabolism , Coronavirus Infections/metabolism , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Amino Acid Transport Systems, Neutral/metabolism , Cell Membrane Permeability , Humans , Membrane Proteins/metabolism , Pandemics , Protein Binding , Receptors, Virus/metabolism , Recombinant Fusion Proteins/metabolism , SARS Virus/metabolism
3.
Emerg Microbes Infect ; 9(1): 1514-1522, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-611844

ABSTRACT

We previously made the hypothesis that STING contributes to COVID-19. The present review detail new arguments for over-activation of STING pathways in COVID-19, following the description of hyper-coagulability and Kawasaki-like diseases in children. Indeed, Kawasaki disease is induced by overreaction of innate cells following exposition to various viruses, including herpes viruses which trigger STING. It predisposes to diffuse vasculitis and aneurysms, whereas STING is over-expressed in arterial aneurisms. The redness at the inoculation site of bacillus Calmette-Guérin, a specific feature of Kawasaki disease, is reproduced by activation of the STING pathway, which is inhibited upstream by aspirin, intravenous immunoglobulins, and Vitamin-D. SARS-CoV2 binding to ACE2 can lead to excessive angiotensin II signaling, which activates the STING pathway in mice. Over-activation of the STING-pathway promotes hyper-coagulability through release of interferon-ß and tissue factor by monocytes-macrophages. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING. Aspirin and dipyridamole may be used, in combination with drugs blocking downstream the activation of the STING pathway, like inhibitors of IL-6R and JAK/STAT pathways. The risk of bleeding should be low as bleeding has not been reported in severe COVID-19 patients.


Subject(s)
Coronavirus Infections/complications , Membrane Proteins/metabolism , Mucocutaneous Lymph Node Syndrome/etiology , Pneumonia, Viral/complications , Angiotensin II/metabolism , Animals , Aspirin/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Dipyridamole/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Interferons/metabolism , Mice , Mucocutaneous Lymph Node Syndrome/metabolism , Pandemics , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Signal Transduction , Thrombosis/drug therapy , Thrombosis/metabolism , Thrombosis/virology
4.
Genes (Basel) ; 11(6)2020 06 11.
Article in English | MEDLINE | ID: covidwho-602760

ABSTRACT

There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing ACE2 and TMPRSS2. Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection.


Subject(s)
Betacoronavirus/metabolism , Enterocytes/metabolism , Lower Gastrointestinal Tract/metabolism , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases/genetics , Base Sequence , Cells, Cultured , Coronavirus Infections/pathology , Enterocytes/virology , Gastrointestinal Diseases/virology , Humans , Lower Gastrointestinal Tract/virology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Sequence Analysis , Serine Endopeptidases/metabolism , Virus Internalization
6.
Sci Immunol ; 5(47)2020 05 13.
Article in English | MEDLINE | ID: covidwho-260039

ABSTRACT

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.


Subject(s)
Betacoronavirus/physiology , Enterocytes/virology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Animals , Cell Line , Duodenum/cytology , Enterocytes/pathology , Humans , Mice , Organoids/virology , Peptidyl-Dipeptidase A/metabolism , Rotavirus/physiology , Vesiculovirus/genetics
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