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2.
Microbiol Spectr ; 10(5): e0105622, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2001788

ABSTRACT

Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has posed a severe threat to global public health. The current study revealed that several inhibitors of protein kinases C (PKCs) possess protective activity against SARS-CoV-2 infection. Four pan-PKC inhibitors, Go 6983, bisindolylmaleimide I, enzastaurin, and sotrastaurin, reduced the replication of a SARS-CoV-2 replicon in both BHK-21 and Huh7 cells. A PKCδ-specific inhibitor, rottlerin, was also effective in reducing viral infection. The PKC inhibitors acted at an early step of SARS-CoV-2 infection. Finally, PKC inhibitors blocked the replication of wild-type SARS-CoV-2 in ACE2-expressing A549 cells. Our work highlights the importance of the PKC signaling pathway in infection by SARS-CoV-2 and provides evidence that PKC-specific inhibitors are potential therapeutic agents against SARS-CoV-2. IMPORTANCE There is an urgent need for effective therapeutic drugs to control the pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). We found that several inhibitors of protein kinases C (PKCs) dramatically decrease the replication of SARS-CoV-2 in cultured cells. These PKC inhibitors interfere with an early step of viral infection. Therefore, the rapid and prominent antiviral effect of PKC inhibitors underscores that they are promising antiviral agents and suggests that PKCs are important host factors involved in infection by SARS-CoV-2.


Subject(s)
Antiviral Agents , Protein Kinase C , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Cells, Cultured , Protein Kinase C/pharmacology , SARS-CoV-2/drug effects , COVID-19 Drug Treatment
3.
Front Psychiatry ; 13: 837399, 2022.
Article in English | MEDLINE | ID: covidwho-1785426

ABSTRACT

Purpose: The purpose of the study was to determine the long-term effects of one-week self-guided internet cognitive behavioral treatments for insomnia (CBTI) on situational insomnia during the COVID-19 pandemic. Patients and Methods: The participants with situational insomnia (n = 194) were recruited from March 2020 to April 2020 in Guangzhou, China. The insomnia severity index (ISI), pre-sleep arousal scale (PSAS), and hospital anxiety and depression scale (HADS) were evaluated at baseline and a one-week internet CBTI program was delivered to all individuals. The participants were divided into the complete treatment group (the participants completed all seven modules of the CBTI course, n = 75), and the incomplete treatment group (the participants completed 0-6 modules of the CBTI course, n = 119). A total of 135 participants completed the post-intervention assessments. At 3 months follow-up, a total of 117 participants (complete treatment group: n = 51; incomplete treatment group: n = 66) completed the assessments of the ISI, PSAS and HADS. The transition rate from situational insomnia to chronic insomnia (duration of insomnia ≥ 3 months and ISI ≥ 8) was calculated in the two groups. Linear mixed effect model was used to investigate the effect of group (between the two groups), time (baseline vs. follow-up), and interaction (group x time) on various questionnaire score. Results: The transition rate from situational insomnia to chronic insomnia was significantly lower in the complete treatment group compared to the incomplete treatment group (27.5%, 14/51 vs. 48.5%, 32/66, p = 0.023). There were significant differences in group effect (p = 0.032), time effect (p = 0.000) and group × time effect (p = 0.048) between the two groups in the ISI total score. The ISI total scores decreased in both groups during follow-up compared to their baseline values, with a greater magnitude of decrease in the complete treatment group. There were no significant group x time effects between the two groups in the PSAS-total score, PSAS-somatic, PSAS-cognitive score, HADS total score, HADS anxiety score or HADS depression score. Conclusion: Our results suggested that one-week self-guided internet CBTI prevented the development of chronic insomnia from situational insomnia during the COVID-19 pandemic.

4.
J Virol ; 96(1): e0149221, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1476391

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021), with various incidences and mortalities among regions/ethnicities. The coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize the angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2. We then applied an integrated approach of genetics, biochemistry, and virology to explore the capacity of select ACE2 variants to bind coronavirus spike proteins and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo. In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity. IMPORTANCE There is considerable variation in disease severity among patients infected with SARS-CoV-2, the virus that causes COVID-19. Human genetic variation can affect disease outcome, and the coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize human ACE2 as the receptor to enter cells. We found that several missense ACE2 single-nucleotide variants (SNVs) that showed significantly altered binding with the spike proteins of SARS-CoV, SARS-CoV-2, and NL63-HCoV. We identified an ACE2 SNP, D355N, that restricts the spike protein-ACE2 interaction and consequently has the potential to protect individuals against SARS-CoV-2 infection. Our study highlights that ACE2 polymorphisms could impact human susceptibility to SARS-CoV-2, which may contribute to ethnic and geographical differences in SARS-CoV-2 spread and pathogenicity.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Angiotensin-Converting Enzyme 2/metabolism , Genetic Variation , Humans , Polymorphism, Single Nucleotide , Protein Binding , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
5.
PLoS Pathog ; 17(3): e1009392, 2021 03.
Article in English | MEDLINE | ID: covidwho-1148252

ABSTRACT

Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. Our study shed more lights into the genetic determinants of ACE2 as the functional receptor of SARS-CoV-2, which facilitates our understanding of viral entry.


Subject(s)
COVID-19/enzymology , COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , Receptors, Virus/genetics , SARS-CoV-2/physiology , Animals , Base Sequence , COVID-19/virology , Host Specificity , Humans , Mice/genetics , Mice/virology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Phascolarctidae/genetics , Phascolarctidae/virology , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Sequence Alignment , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
6.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1117490

ABSTRACT

The pandemic of COVID-19, caused by SARS-CoV-2, is a major global health threat. Epidemiological studies suggest that bats (Rhinolophus affinis) are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. By analyzing the conservation of five residues in two virus-binding hotspots of ACE2 (hotspot 31Lys and hotspot 353Lys), we predicted 80 ACE2 proteins from mammals that could potentially mediate SARS-CoV-2 entry. We chose 48 ACE2 orthologs among them for functional analysis, and showed that 44 of these orthologs-including domestic animals, pets, livestock, and animals commonly found in zoos and aquaria-could bind the SARS-CoV-2 spike protein and support viral entry. In contrast, New World monkey ACE2 orthologs could not bind the SARS-CoV-2 spike protein and support viral entry. We further identified the genetic determinant of New World monkey ACE2 that restricts viral entry using genetic and functional analyses. These findings highlight a potentially broad host tropism of SARS-CoV-2 and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, underscoring the necessity to monitor susceptible hosts to prevent future outbreaks.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/veterinary , Receptors, Virus/genetics , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Host Specificity , Humans , Pandemics/prevention & control , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Phylogeny , Protein Binding , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism , Viral Zoonoses/genetics , Viral Zoonoses/prevention & control , Viral Zoonoses/virology , Virus Attachment , Virus Internalization
7.
Nat Commun ; 12(1): 961, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1078585

ABSTRACT

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.


Subject(s)
COVID-19/virology , CRISPR-Cas Systems , Genome-Wide Association Study , Host-Pathogen Interactions , SARS-CoV-2/physiology , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , Chlorocebus aethiops , Disease Models, Animal , Endosomes/virology , HeLa Cells , Humans , Mesocricetus , Serine Endopeptidases , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
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