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1.
Nat Commun ; 12(1): 1112, 2021 02 18.
Article in English | MEDLINE | ID: covidwho-1091491

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.


Subject(s)
/diagnosis , Interleukin-3/blood , Animals , Chemokine CXCL12/immunology , Dendritic Cells/cytology , Disease Models, Animal , Female , Germany , Humans , Immunity, Innate , Interferons/blood , Lung/immunology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Prospective Studies , Severity of Illness Index , T-Lymphocytes/cytology , Viral Load
2.
Mol Med Rep ; 23(4): 1, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1083893

ABSTRACT

Recently, severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS­CoV­2)­causing CoV disease 2019 (COVID­19) emerged in China and has become a global pandemic. SARS­CoV­2 is a novel CoV originating from ß­CoVs. Major distinctions in the gene sequences between SARS­CoV and SARS­CoV­2 include the spike gene, open reading frame (ORF) 3b and ORF 8. SARS­CoV­2 infection is initiated when the virus interacts with angiotensin­converting enzyme 2 (ACE2) receptors on host cells. Through this mechanism, the virus infects the alveolar, esophageal epithelial, ileum, colon and other cells on which ACE2 is highly expressed, causing damage to target organs. To date, host innate immunity may be the only identified direct factor associated with viral replication. However, increased ACE2 expression may upregulate the viral load indirectly by increasing the baseline level of infectious virus particles. The peak viral load of SARS­CoV­2 is estimated to occur ~10 days following fever onset, causing patients in the acute stage to be the primary infection source. However, patients in the recovery stage or with occult infections can also be contagious. The host immune response in patients with COVID­19 remains to be elucidated. By studying other SARS and Middle East respiratory syndrome coronaviruses, it is hypothesized that patients with COVID­19 may lack sufficient antiviral T­cell responses, which consequently present with innate immune response disorders. This may to a certain degree explain why this type of CoV triggers severe inflammatory responses and immune damage and its associated complications.


Subject(s)
/pathology , /physiology , Adaptive Immunity , /immunology , Humans , Immunity, Innate , /immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Load
3.
Front Public Health ; 8: 593491, 2020.
Article in English | MEDLINE | ID: covidwho-1081109

ABSTRACT

Background: SARS-CoV-2-infected subjects have been proven contagious in the symptomatic, pre-symptomatic and asymptomatic phase. The identification of these patients is crucial in order to prevent virus circulation. No reliable data on the sensitivity of nasopharyngeal swabs (NPS) are available because of the lack of a shared reference standard to identify SARS-CoV-2 infected patients. The aim of our study was to collect data on patients with a known diagnosis of COVID-19 who underwent serial testing to assess NPS sensitivity. Methods: The study was a multi-center, observational, retrospective clinical study with consecutive enrollment. We enrolled patients who met all of the following inclusion criteria: clinical recovery, documented SARS-CoV-2 infection (≥1 positive rRT-PCR result) and ≥1 positive NPS among the first two follow-up swabs. A positive NPS not preceded by a negative nasopharyngeal swab collected 24-48 h earlier was considered a true positive. A negative NPS followed by a positive NPS collected 24-48 h later was regarded as a false negative. The primary outcome was to define sensitivity of SARS-CoV-2 detection with NPS. Results: Three hundred and ninety three NPS were evaluated in 233 patients; the sensitivity was 77% (95% CI, 73 to 81%). Sensitivity of the first follow-up NPS (n = 233) was 79% (95% CI, 73 to 84%) with no significant variations over time. We found no statistically significant differences in the sensitivity of the first follow-up NPS according to time since symptom onset, age, sex, number of comorbidities, and onset symptoms. Conclusions: NPS utility in the diagnostic algorithm of COVID-19 should be reconsidered.


Subject(s)
/methods , Nasopharynx/virology , /isolation & purification , Adult , Aged , /instrumentation , Chi-Square Distribution , Female , Humans , Male , Middle Aged , RNA, Viral/analysis , Retrospective Studies , Sensitivity and Specificity , Viral Load
4.
Nat Commun ; 12(1): 944, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1078588

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6-9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , /immunology , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Antibodies, Viral/genetics , Antibodies, Viral/immunology , Chlorocebus aethiops , Female , Immunoglobulin G/administration & dosage , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , /physiology , Seroconversion , Vero Cells , Viral Load
5.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Article in English | MEDLINE | ID: covidwho-1075324

ABSTRACT

COVID-19 transmits by droplets generated from surfaces of airway mucus during processes of respiration within hosts infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. We studied respiratory droplet generation and exhalation in human and nonhuman primate subjects with and without COVID-19 infection to explore whether SARS-CoV-2 infection, and other changes in physiological state, translate into observable evolution of numbers and sizes of exhaled respiratory droplets in healthy and diseased subjects. In our observational cohort study of the exhaled breath particles of 194 healthy human subjects, and in our experimental infection study of eight nonhuman primates infected, by aerosol, with SARS-CoV-2, we found that exhaled aerosol particles vary between subjects by three orders of magnitude, with exhaled respiratory droplet number increasing with degree of COVID-19 infection and elevated BMI-years. We observed that 18% of human subjects (35) accounted for 80% of the exhaled bioaerosol of the group (194), reflecting a superspreader distribution of bioaerosol analogous to a classical 20:80 superspreader of infection distribution. These findings suggest that quantitative assessment and control of exhaled aerosol may be critical to slowing the airborne spread of COVID-19 in the absence of an effective and widely disseminated vaccine.


Subject(s)
/physiopathology , Exhalation/physiology , Obesity/physiopathology , Aerosols , Age Factors , Animals , Body Mass Index , /virology , Cohort Studies , Humans , Mucus/chemistry , Mucus/virology , Obesity/epidemiology , Obesity/virology , Particle Size , Primates , Respiratory System/metabolism , Viral Load
8.
Gut Microbes ; 13(1): 1-9, 2021.
Article in English | MEDLINE | ID: covidwho-1069185

ABSTRACT

Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells' permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.


Subject(s)
/virology , Fatty Acids, Volatile/metabolism , Gastrointestinal Microbiome , Intestinal Mucosa/virology , Adult , Aged , Caco-2 Cells , Colon/virology , Epithelial Cells/virology , Female , Humans , In Vitro Techniques , Male , Middle Aged , /physiology , Viral Load , Virus Internalization , Young Adult
9.
Immunity ; 54(1): 44-52.e3, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-1065202

ABSTRACT

Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Programmed Cell Death 1 Receptor/metabolism , /immunology , Acute-Phase Reaction/immunology , Acute-Phase Reaction/virology , /virology , Convalescence , Epitopes, T-Lymphocyte , Histocompatibility Antigens Class I/immunology , Humans , Immunologic Memory , Immunophenotyping , Interferon-gamma/metabolism , Lymphocyte Activation , Viral Load
13.
Antiviral Res ; 186: 105012, 2021 02.
Article in English | MEDLINE | ID: covidwho-1064809

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, a severe respiratory disease with varying clinical presentations and outcomes, and responsible for a major pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against multiple RNA viruses including coronaviruses. Specifically, rocaglates inhibit eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. Here, we assessed the antiviral activity of the synthetic rocaglate CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In primary human airway epithelial cells, CR-31-B (-) reduced viral titers to undetectable levels at a concentration of 100 nM. Reduced virus reproduction was accompanied by substantially reduced viral protein accumulation and replication/transcription complex formation. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , /physiology , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Bronchi/virology , Cells, Cultured , Chlorocebus aethiops , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Humans , Respiratory Mucosa/virology , Vero Cells , Viral Load/drug effects , /drug effects
14.
Epidemiol Prev ; 44(5-6 Suppl 2): 152-159, 2020.
Article in English | MEDLINE | ID: covidwho-1068135

ABSTRACT

The determinants of the risk of becoming infected by SARS-CoV-2, contracting COVID-19, and being affected by the more serious forms of the disease have been generally explored in merely qualitative terms. It seems reasonable to argue that the risk patterns for COVID-19 have to be usefully studied in quantitative terms too, whenever possible applying the same approach to the relationship 'dose of the exposure vs pathological response' commonly used for chemicals and already followed for several biological agents to SARS-CoV-2, too. Such an approach is of particular relevance in the fields of both occupational epidemiology and occupational medicine, where the identification of the sources of a dangerous exposure and of the web of causation of a disease is often questionable and questioned: it is relevant when evaluating the population risk, too. Specific occupational scenarios, basically involving health workers, exhibit important proportions of both subjects simply infected by SARS-CoV-2 and of ill subjects with, respectively, mild, moderate, and severe disease. Similar patterns have been described referring to various circumstances of community exposure, e.g., standing in crowded public places, travelling on crowded means of transport, living in accommodation or care homes, living in the same household as a COVID-19 case. The hypothesis that these findings are a consequence not only of high probabilities of exposure, but also of high doses (as a product of both intensity and duration, with possible autonomous effects of peaks of exposure) deserves to be systematically tested, in order to reconstruct the web of causation of COVID-19 individual and clustered cases and to cope with situations at critical risk for SARS-CoV-2, needing to be identified, mapped, and dealt with at the right time. A limited but consistent set of papers supporting these assumptions has been traced in the literature. Under these premises, the creation of a structured inventory of both values of viral concentrations in the air (in case and if possible, of surface contaminations too) and of viral loads in biological matrixes is proposed, with the subsequent construction of a scenario-exposure matrix. A scenario-exposure matrix for SARS-CoV-2 may represent a useful tool for research and practical risk management purposes, helping to understand the possibly critical circumstances for which no direct exposure measure is available (this is an especially frequent case, in contexts of low socio-economic level) and providing guidance to determine evidence-based public health strategies.


Subject(s)
/virology , Environmental Exposure , Viral Load , Viremia/virology , Aerosols , Air Microbiology , Air Pollution, Indoor , /epidemiology , Cross Infection/epidemiology , Cross Infection/transmission , Cross Infection/virology , Crowding , Disease Transmission, Infectious , Environmental Monitoring , Family Characteristics , Fomites/virology , Humans , Infectious Disease Transmission, Patient-to-Professional , Institutionalization , Occupational Exposure , Risk , Risk Assessment , Time Factors , Transportation
15.
J Glob Health ; 10(2): 021101, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1067956

ABSTRACT

Background: Understanding carriage and transmission potential of SARS-CoV-2 in children is of paramount importance to understand the spread of virus in school and community settings. Methods: We performed an updated rapid review to investigate the role of children in the transmission of SARS-CoV-2. We synthesized evidence for five categories and results are reported narratively. Results: A total of 33 new studies were included for this review. We did not identify additional studies that reported documented cases of SARS-CoV-2 transmission by children. We identified 15 new studies that demonstrate children's susceptibility and transmission risk of SARS-CoV-2 with evidence provided on the chance of being index or secondary cases, the potential of faecal-oral transmission, and the possibility of asymptomatic transmission. There is little data on the transmission of SARS-CoV-2 in schools. There were three studies reporting COVID-19 school outbreaks in France (Oise), Australia (New South Wales) and Israel. The remaining four studies found that all reported cases did not infect any other pupils or staff. With data from seven studies and governmental websites, the proportion of children among all confirmed COVID-19 patients was estimated for 29 countries, varying from 0.3% (lowest in Spain) up to 13.8% (highest in Argentina). Lastly, we identified seven studies reporting on PIMS-TS linked to COVID-19 among paediatric patients. Conclusions: There is somewhat limited evidence available for quantifying the extent to which children may contribute to overall transmission, but the balance of evidence so far suggests that children and schools play only a limited role in overall transmission.


Subject(s)
/epidemiology , Schools/statistics & numerical data , Adolescent , Age Factors , Child , Child, Preschool , Disease Outbreaks , Feces/virology , Female , Global Health , Humans , Male , Seroepidemiologic Studies , Systemic Inflammatory Response Syndrome/epidemiology , Viral Load
16.
Viruses ; 13(1)2021 Jan 15.
Article in English | MEDLINE | ID: covidwho-1067778

ABSTRACT

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.


Subject(s)
Asymptomatic Diseases , Disease Models, Animal , /physiology , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , /pathology , Female , Ferrets , Genome, Viral/genetics , Mutation , Nasal Mucosa/virology , RNA, Viral/genetics , Viral Load , Virus Shedding
18.
JCI Insight ; 6(1)2021 01 11.
Article in English | MEDLINE | ID: covidwho-1066996

ABSTRACT

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross-SARS-reactive antibody, CR3022, was assessed. CR3022 was able to broadly drive antibody effector functions, providing critical immune clearance at entry and upon egress. Using selectively engineered Fc variants, no protection was observed after administration of WT IgG1 in mice or hamsters. Conversely, the functionally enhanced Fc variant resulted in increased pathology in both the mouse and hamster models, causing weight loss in mice and enhanced viral replication and weight loss in the more susceptible hamster model, highlighting the pathological functions of Fc-enhancing mutations. These data point to the critical need for strategic Fc engineering for the treatment of SARS-CoV-2 infection.


Subject(s)
Antibodies, Neutralizing/pharmacology , Immunity, Innate/drug effects , Immunoglobulin Fc Fragments/genetics , Immunoglobulin G/pharmacology , Virus Replication/drug effects , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/therapeutic use , /physiopathology , Cricetinae , Cross Reactions , Epitopes , Humans , Immunity, Innate/immunology , Immunoglobulin G/genetics , Immunoglobulin G/therapeutic use , Mesocricetus , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/immunology , Protein Engineering , Receptors, Fc/immunology , SARS Virus/drug effects , SARS Virus/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology , THP-1 Cells , Viral Load/drug effects , Weight Loss/drug effects
19.
Sci Adv ; 7(2)2021 01.
Article in English | MEDLINE | ID: covidwho-1066788

ABSTRACT

Point-of-care COVID-19 assays that are more sensitive than the current RT-PCR (reverse transcription polymerase chain reaction) gold standard assay are needed to improve disease control efforts. We describe the development of a portable, ultrasensitive saliva-based COVID-19 assay with a 15-min sample-to-answer time that does not require RNA isolation or laboratory equipment. This assay uses CRISPR-Cas12a activity to enhance viral amplicon signal, which is stimulated by the laser diode of a smartphone-based fluorescence microscope device. This device robustly quantified viral load over a broad linear range (1 to 105 copies/µl) and exhibited a limit of detection (0.38 copies/µl) below that of the RT-PCR reference assay. CRISPR-read SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) RNA levels were similar in patient saliva and nasal swabs, and viral loads measured by RT-PCR and the smartphone-read CRISPR assay demonstrated good correlation, supporting the potential use of this portable assay for saliva-based point-of-care COVID-19 diagnosis.


Subject(s)
/diagnosis , Point-of-Care Testing , Saliva/virology , Smartphone , Animals , CRISPR-Cas Systems , Chlorocebus aethiops , Computer Simulation , Female , Humans , Limit of Detection , Macaca mulatta , Male , Molecular Diagnostic Techniques/instrumentation , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity , Vero Cells , Viral Load
20.
Proc Natl Acad Sci U S A ; 118(8)2021 02 23.
Article in English | MEDLINE | ID: covidwho-1066042

ABSTRACT

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients (P < 10-4). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, P < 10-3). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.


Subject(s)
/mortality , Models, Theoretical , Nasopharynx/virology , RNA, Viral/analysis , Viral Load , Aged , Antibodies, Viral/blood , /epidemiology , Female , France/epidemiology , Hospitalization , Humans , Kinetics , Male , Prognosis , Prospective Studies , RNA, Viral/genetics , Risk Factors , Survival Rate
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