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1.
Int J Mol Sci ; 24(4)2023 Feb 07.
Article in English | MEDLINE | ID: covidwho-2232892

ABSTRACT

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.


Subject(s)
COVID-19 , Male , Humans , COVID-19/metabolism , SARS-CoV-2/metabolism , Peptidyl-Dipeptidase A/metabolism , Lung/metabolism , Epithelial Cells/metabolism , Virus Internalization
2.
Sci Rep ; 12(1): 21053, 2022 Dec 06.
Article in English | MEDLINE | ID: covidwho-2151107

ABSTRACT

The 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.

3.
J Extracell Vesicles ; 11(10): e12269, 2022 10.
Article in English | MEDLINE | ID: covidwho-2084354

ABSTRACT

Small Extracellular Vesicles (sEVs) are 50-200 nm in diameter vesicles delimited by a lipid bilayer, formed within the endosomal network or derived from the plasma membrane. They are secreted in various biological fluids, including airway nasal mucus. The goal of this work was to understand the role of sEVs present in the mucus (mu-sEVs) produced by human nasal epithelial cells (HNECs) in SARS-CoV-2 infection. We show that uninfected HNECs produce mu-sEVs containing SARS-CoV-2 receptor ACE2 and activated protease TMPRSS2. mu-sEVs cleave prefusion viral Spike proteins at the S1/S2 boundary, resulting in higher proportions of prefusion S proteins exposing their receptor binding domain in an 'open' conformation, thereby facilitating receptor binding at the cell surface. We show that the role of nasal mu-sEVs is to complete prefusion Spike priming performed by intracellular furin during viral egress from infected cells. This effect is mediated by vesicular TMPRSS2 activity, rendering SARS-CoV-2 virions prone to entry into target cells using the 'early', TMPRSS2-dependent pathway instead of the 'late', cathepsin-dependent route. These results indicate that prefusion Spike priming by mu-sEVs in the nasal cavity plays a role in viral tropism. They also show that nasal mucus does not protect from SARS-CoV-2 infection, but instead facilitates it.


Subject(s)
COVID-19 , Extracellular Vesicles , Humans , Spike Glycoprotein, Coronavirus/chemistry , Furin , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , Proviruses/metabolism , Lipid Bilayers , Virus Internalization , Epithelial Cells/metabolism , Extracellular Vesicles/metabolism , Cathepsins
5.
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale ; 2022.
Article in English | ScienceDirect | ID: covidwho-1821099

ABSTRACT

Résumé Objectif: Évaluer l’impact des trois premières vagues de Covid-19 sur la formation théorique et pratique des étudiants en DES ORL&CCF (ou internes) en France. Matériel et méthodes: Étude observationnelle, rétrospective. Un questionnaire contenant 55 items relatifs à la formation pratique et théorique a été envoyé aux internes d’ORL&CCF de cinq grandes régions françaises (Ile-de-France, Rhône-Alpes Auvergne, Occitanie, Grand Est, Grand Ouest) d’août à octobre 2021. Résultats: 89/135 internes (66%) ont répondu au questionnaire. Deux tiers des internes estimaient que la formation pratique chirurgicale était la plus impactée, devant la formation théorique, avec une réduction évaluée à 50-75%, 25-50% et 0-25% pour les trois premières vagues, respectivement. Les internes d’Ile-de-France, Rhône-Alpes Auvergne et Grand Est étaient les plus touchés par la première vague (réduction de 75-100% de l’activité chirurgicale, en parallèle d’un nombre d’hospitalisations élevé). L’otologie, la rhinologie et les explorations fonctionnelles ont été les plus impactées par la crise sanitaire, tandis que la pédiatrie et la cancérologie ont été épargnées. 71/89 internes (79,7%) estimaient que la première vague a impacté leur formation professionnelle, tandis que cette proportion se réduisait à 39,3% et 44,9% pour les deuxième et troisième vagues, respectivement. Conclusion: La première vague de Covid-19, comparée aux deux suivantes, a sévèrement impacté la formation chirurgicale des étudiants en DES ORL&CCF français, spécialement dans les régions gravement frappées par la pandémie, tandis que la formation théorique a été relativement épargnée par la mise en place d’alternatives pédagogiques en distanciel.

6.
Occup Environ Med ; 2020 Dec 04.
Article in English | MEDLINE | ID: covidwho-961125

ABSTRACT

OBJECTIVES: Although healthcare workers (HCWs) have been particularly affected by SARS-CoV-2, detailed data remain scarce. In this study, we investigated infection rates, clinical characteristics, occupational exposure and household transmission among all symptomatic HCWs screened by SARS-CoV-2 RT-PCR between 17 March (French lockdown) and 20 April. METHODS: SARS-CoV-2 RT-PCR was proposed to symptomatic (new cough or dyspnoea) HCWs at Creteil Hospital in one of the Parisian suburbs most severely affected by COVID-19. Data on occupational profile, living situation and household, together with self-isolation and mask use at home were collected, as well as the number of cases in the household. RESULTS: The incidence rate of symptomatic SARS-CoV-2 was estimated to be 5% (110/2188). A total of 110 (35%) of the 314 HCWs tested positive and 9 (8%) were hospitalised. On multivariate analysis, factors independently associated with positive RT-PCR were occupational profile with direct patient facing (OR 3.1, 95% CI 1.1 to 8.8), p<0.03), and presence of anosmia (OR 5.7, 95% CI 3.1 to 10.6), p<0.0001). Being a current smoker was associated with negative RT-PCR (OR 0.3, 95% CI 0.1 to 0.7), p=0.005). Transmission from HCWs to household members was reported in 9 (14%) cases, and 2 deaths occurred. Overall, self-isolation was possible in 52% of cases, but only 31% of HCWs were able to wear a mask at home. CONCLUSION: This is the first study to report infection rates among HCWs during the peak of the SARS-CoV-2 epidemic in France and the lockdown period, highlighting the risk related to occupational profile and household transmission.

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