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1.
PLoS Pathog ; 18(6): e1010620, 2022 06.
Article in English | MEDLINE | ID: covidwho-1892334

ABSTRACT

Intestinal microbial metabolites have been increasingly recognized as important regulators of enteric viral infection. However, very little information is available about which specific microbiota-derived metabolites are crucial for swine enteric coronavirus (SECoV) infection in vivo. Using swine acute diarrhea syndrome (SADS)-CoV as a model, we were able to identify a greatly altered bile acid (BA) profile in the small intestine of infected piglets by untargeted metabolomic analysis. Using a newly established ex vivo model-the stem cell-derived porcine intestinal enteroid (PIE) culture-we demonstrated that certain BAs, cholic acid (CA) in particular, enhance SADS-CoV replication by acting on PIEs at the early phase of infection. We ruled out the possibility that CA exerts an augmenting effect on viral replication through classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling, innate immune suppression or viral attachment. BA induced multiple cellular responses including rapid changes in caveolae-mediated endocytosis, endosomal acidification and dynamics of the endosomal/lysosomal system that are critical for SADS-CoV replication. Thus, our findings shed light on how SECoVs exploit microbiome-derived metabolite BAs to swiftly establish viral infection and accelerate replication within the intestinal microenvironment.


Subject(s)
Alphacoronavirus , Coronavirus Infections , Swine Diseases , Alphacoronavirus/physiology , Animals , Bile Acids and Salts , Caveolae , Diarrhea , Swine
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322523

ABSTRACT

Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that fibrinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent inflammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identified as a fibrinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the first endogenous inhibitor of LTA4H, a pro-inflammatory enzyme catalyzing final and rating limited step in biosynthesis of leukotriene-B4 that is an extremely inflammatory mediator and a target to design superior anti-inflammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and fibrinogen expression in vivo. Collectively, these findings identify the imbalance between inflammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior anti-inflammatory function because it specifically targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H’s aminopeptidase activity.

3.
Cell Res ; 31(1): 17-24, 2021 01.
Article in English | MEDLINE | ID: covidwho-953056

ABSTRACT

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Teicoplanin/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Caco-2 Cells , Chlorocebus aethiops , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Protein Binding/drug effects , Teicoplanin/pharmacokinetics , Teicoplanin/pharmacology , Vero Cells
4.
Infect Dis Poverty ; 9(1): 148, 2020 Oct 26.
Article in English | MEDLINE | ID: covidwho-892372

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has been affecting people's psychosocial health and well-being through various complex pathways. The present study aims to investigate the perceived psychosocial health and its sociodemographic correlates among Chinese community-dwelling residents. METHODS: This cross-sectional survey was carried out online and using a structured questionnaire during April 2020. In total, 4788 men and women with the age range of 11-98 years from eight provinces in eastern, central and western China were included in the analysis. We adopted a tactical approach to capture three key domains of perceived psychosocial health that are more likely to occur during a pandemic including hopelessness, loneliness, and depression. Multiple regression method, binary logistic regression model and variance inflation factor (VIF) were used to conduct data analysis. RESULTS: Respectively 34.8%, 32.5% and 44.8% of the participants expressed feeling more hopeless, lonely, and depressed during the pandemic. The percentage of all three indicators was comparatively higher among women than among men: hopelessness (50.7% vs 49.3%), loneliness (52.4% vs 47.6%), and depression (56.2% vs 43.8%). Being married was associated with lower odds of loneliness among men (odds ratio [OR] = 0.63, 95% CI: 0.45-0.90). Loneliness was negatively associated with smoking (OR = 0.67, 95% CI: 0.45-0.99) and positively associated with drinking (OR = 1.45, 95% CI: 1.04-2.02). Compared with those in the lowest income bracket (< CNY 10 000), men (OR = 0.34, 95% CI: 0.21-0.55) and women (OR = 0.36, 95% CI: 0.23-0.56) in the highest level of annually housed income (> CNY 40 000) had the lowest odds of reporting perceived hopelessness (OR = 0.35, 95% CI: 0.25-0.48). Smoking also showed negative association with depression only among men (OR = 0.63, 95% CI: 0.43-0.91). CONCLUSIONS: More than one-third of the participants reported worsening in the experience of hopelessness and loneliness, with more than two-fifth of worsening depression during the pandemic compared with before the outbreak. Several socioeconomic and lifestyle factors were found to be associated with the outcome variables, most notably participants' marital status, household income, smoking, alcohol drinking, existing chronic conditions. These findings may be of significance to treat patients and help them recover from the pandemic.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/psychology , Depression/epidemiology , Loneliness/psychology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/psychology , Self Concept , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus/isolation & purification , COVID-19 , Child , China/epidemiology , Cross-Sectional Studies , Depression/psychology , Depression/virology , Female , Humans , Logistic Models , Male , Mental Health , Middle Aged , Pandemics , Prevalence , Regression Analysis , SARS-CoV-2 , Socioeconomic Factors , Surveys and Questionnaires , Young Adult
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