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1.
PLoS Pathog ; 17(12): e1010106, 2021 12.
Article in English | MEDLINE | ID: covidwho-1598647

ABSTRACT

The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.


Subject(s)
COVID-19/virology , Influenza, Human/virology , Orthomyxoviridae/physiology , SARS-CoV-2/physiology , Animals , Antiviral Agents , COVID-19/therapy , COVID-19/transmission , Drug Development , Evolution, Molecular , Humans , Influenza, Human/therapy , Influenza, Human/transmission , Orthomyxoviridae/immunology , SARS-CoV-2/immunology , Selection, Genetic , Viral Load , Viral Vaccines
2.
Viruses ; 13(9)2021 09 12.
Article in English | MEDLINE | ID: covidwho-1411086

ABSTRACT

Our therapeutic arsenal against viruses is very limited and the current pandemic of SARS-CoV-2 highlights the critical need for effective antivirals against emerging coronaviruses. Cellular assays allowing a precise quantification of viral replication in high-throughput experimental settings are essential to the screening of chemical libraries and the selection of best antiviral chemical structures. To develop a reporting system for SARS-CoV-2 infection, we generated cell lines expressing a firefly luciferase maintained in an inactive form by a consensus cleavage site for the viral protease 3CLPro of coronaviruses, so that the luminescent biosensor is turned on upon 3CLPro expression or SARS-CoV-2 infection. This cellular assay was used to screen a metabolism-oriented library of 492 compounds to identify metabolic vulnerabilities of coronaviruses for developing innovative therapeutic strategies. In agreement with recent reports, inhibitors of pyrimidine biosynthesis were found to prevent SARS-CoV-2 replication. Among the top hits, we also identified the NADPH oxidase (NOX) inhibitor Setanaxib. The anti-SARS-CoV-2 activity of Setanaxib was further confirmed using ACE2-expressing human pulmonary cells Beas2B as well as human primary nasal epithelial cells. Altogether, these results validate our cell-based functional assay and the interest of screening libraries of different origins to identify inhibitors of SARS-CoV-2 for drug repurposing or development.


Subject(s)
Antiviral Agents/isolation & purification , Biosensing Techniques/methods , Coronavirus 3C Proteases/metabolism , SARS-CoV-2/physiology , Virus Replication , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Drug Discovery , Drug Evaluation, Preclinical , Enzyme Activation , HEK293 Cells , Humans , Luciferases, Firefly/metabolism , Nasal Mucosa/virology , Pyrazolones/pharmacology , Pyridones/pharmacology , SARS-CoV-2/metabolism , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
4.
Nat Immunol ; 22(3): 322-335, 2021 03.
Article in English | MEDLINE | ID: covidwho-1060966

ABSTRACT

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Subject(s)
COVID-19/immunology , Interferon-alpha/immunology , Interleukin-18/immunology , Macrophages/immunology , Monocytes/immunology , Mucosal-Associated Invariant T Cells/immunology , Adult , Aged , Aged, 80 and over , Animals , Bronchoalveolar Lavage , Case-Control Studies , Chlorocebus aethiops , Cohort Studies , Female , France , Humans , Immunophenotyping , Interleukin-10/immunology , Interleukin-15/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Male , Middle Aged , RNA-Seq , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis , Vero Cells , Young Adult
6.
Front Med (Lausanne) ; 7: 584036, 2020.
Article in English | MEDLINE | ID: covidwho-914431

ABSTRACT

Background: The coronavirus infectious disease-2019 (COVID-19) pandemic has led to an unprecedented shortage of healthcare resources, primarily personal protective equipment like surgical masks, and N95/filtering face piece type 2 (FFP2) respirators. Objective: Reuse of surgical masks and N95/FFP2 respirators may circumvent the supply chain constraints and thus overcome mass shortage. Methods, design, setting, and measurement: Herein, we tested the effects of dry- and moist-air controlled heating treatment on structure and chemical integrity, decontamination yield, and filtration performance of surgical masks and FFP2 respirators. Results: We found that treatment in a climate chamber at 70°C during 1 h with 75% humidity rate was adequate for enabling substantial decontamination of both respiratory viruses, oropharyngeal bacteria, and model animal coronaviuses, while maintaining a satisfying filtering capacity. Limitations: Further studies are now required to confirm the feasibility of the whole process during routine practice. Conclusion: Our findings provide compelling evidence for the recycling of pre-used surgical masks and N95/FFP2 respirators in case of imminent mass shortfall.

7.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-744478

ABSTRACT

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/immunology , Mucosal-Associated Invariant T Cells/metabolism , Natural Killer T-Cells/metabolism , Phenotype , Pneumonia, Viral/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Respiratory Distress Syndrome/immunology , Aged , Antigens, CD/blood , Antigens, Differentiation, T-Lymphocyte/blood , COVID-19 , Cells, Cultured , Coronavirus Infections/virology , Cytokines/metabolism , Female , Humans , Inflammation/immunology , Inflammation/metabolism , Lectins, C-Type/blood , Male , Middle Aged , Mucosal-Associated Invariant T Cells/immunology , Natural Killer T-Cells/immunology , Pandemics , Pneumonia, Viral/virology , Prognosis , Prospective Studies , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Severity of Illness Index
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