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1.
Nat Microbiol ; 7(2): 213-223, 2022 02.
Article in English | MEDLINE | ID: covidwho-1621245

ABSTRACT

The major transmission route for SARS-CoV-2 is airborne. However, previous studies could not elucidate the contribution between large droplets and aerosol transmission of SARS-CoV-2 and its variants. Here, we designed and validated an optimized transmission caging setup, which allows for the assessment of aerosol transmission efficiency at various distances. At a distance of 2 m, only particles of <5 µm traversed between cages. Using this setup, we investigated the relative efficiency of aerosol transmission between the SARS-CoV-2 Alpha variant (B.1.1.7) and lineage A in Syrian hamsters. Aerosol transmission of both variants was confirmed in all sentinels after 24 h of exposure as demonstrated by respiratory virus shedding and seroconversion. Productive transmission also occurred after 1 h of exposure, highlighting the efficiency of this transmission route. Interestingly, after donors were infected with a mix of both variants, the Alpha variant outcompeted the lineage A variant in an airborne transmission chain. Overall, these data indicate that a lower infectious dose of the Alpha variant, compared to lineage A, could be sufficient for successful transmission. This highlights the continuous need to assess emerging variants and the development for pre-emptive transmission mitigation strategies.


Subject(s)
COVID-19/transmission , SARS-CoV-2/genetics , Aerosols , Animals , COVID-19/virology , Female , Male , Mesocricetus , SARS-CoV-2/pathogenicity , Viral Load , Virus Shedding
2.
Viruses ; 13(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572667

ABSTRACT

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.


Subject(s)
COVID-19 , Diet, High-Fat/adverse effects , Dietary Carbohydrates/adverse effects , Lipid Metabolism , Severity of Illness Index , Animals , COVID-19/pathology , Cricetinae , Cytokines/blood , Disease Models, Animal , Edema , Fibrin , Hemorrhage , Humans , Interleukin-10 , Interleukin-6 , Lipidomics , Lipids/blood , Liver/pathology , Lung/pathology , Male , Mesocricetus , Obesity , SARS-CoV-2 , Sugars , Vasculitis/pathology , Virus Shedding
3.
[Unspecified Source]; 2020.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292809

ABSTRACT

SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 10 (4) TCID (50) or 10 (5) TCID (50) , the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10 (5) TCID (50) group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Taken together, this suggests that this mouse model can be useful for studies of pathogenesis and medical countermeasure development. AUTHORS SUMMARY: The disease manifestation of COVID-19 in humans range from asymptomatic to severe. While several mild to moderate disease models have been developed, there is still a need for animal models that recapitulate the severe and fatal progression observed in a subset of patients. Here, we show that humanized transgenic mice developed dose-dependent disease when inoculated with SARS-CoV-2, the etiological agent of COVID-19. The mice developed upper and lower respiratory tract infection, with virus replication also in the brain after day 3 post inoculation. The pathological and immunological diseases manifestation observed in these mice bears resemblance to human COVID-19, suggesting increased usefulness of this model for elucidating COVID-19 pathogenesis further and testing of countermeasures, both of which are urgently needed.

4.
Nat Commun ; 12(1): 4985, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361633

ABSTRACT

Transmission of SARS-CoV-2 is driven by contact, fomite, and airborne transmission. The relative contribution of different transmission routes remains subject to debate. Here, we show Syrian hamsters are susceptible to SARS-CoV-2 infection through intranasal, aerosol and fomite exposure. Different routes of exposure present with distinct disease manifestations. Intranasal and aerosol inoculation causes severe respiratory pathology, higher virus loads and increased weight loss. In contrast, fomite exposure leads to milder disease manifestation characterized by an anti-inflammatory immune state and delayed shedding pattern. Whereas the overall magnitude of respiratory virus shedding is not linked to disease severity, the onset of shedding is. Early shedding is linked to an increase in disease severity. Airborne transmission is more efficient than fomite transmission and dependent on the direction of the airflow. Carefully characterized SARS-CoV-2 transmission models will be crucial to assess potential changes in transmission and pathogenic potential in the light of the ongoing SARS-CoV-2 evolution.


Subject(s)
COVID-19/transmission , Fomites , Administration, Intranasal , Aerosols , Animals , COVID-19/blood , COVID-19/virology , Cytokines/blood , Female , High-Throughput Nucleotide Sequencing , Lung/virology , Mesocricetus , Nasal Cavity/virology , Particle Size , RNA, Viral/genetics , Respiratory System/virology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Vaccination , Virus Replication , Virus Shedding
6.
PLoS Pathog ; 17(1): e1009195, 2021 01.
Article in English | MEDLINE | ID: covidwho-1034958

ABSTRACT

SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 102 TCID50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/pathology , Keratin-18/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Female , Humans , Keratin-18/immunology , Lung/immunology , Lung/pathology , Lymphocytes/immunology , Macrophages/immunology , Male , Mice , Mice, Transgenic , Promoter Regions, Genetic , SARS-CoV-2/physiology , Trachea/immunology , Trachea/virology
8.
Cell ; 183(7): 1901-1912.e9, 2020 12 23.
Article in English | MEDLINE | ID: covidwho-950119

ABSTRACT

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.


Subject(s)
COVID-19/immunology , Common Variable Immunodeficiency/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , SARS-CoV-2/isolation & purification , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/complications , COVID-19/virology , Common Variable Immunodeficiency/blood , Common Variable Immunodeficiency/complications , Common Variable Immunodeficiency/virology , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/virology , Respiratory Tract Infections/blood , Respiratory Tract Infections/complications , Respiratory Tract Infections/immunology , Respiratory Tract Infections/virology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
9.
Nature ; 586(7830): 578-582, 2020 10.
Article in English | MEDLINE | ID: covidwho-691215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic3. Vaccines are an essential countermeasure and are urgently needed to control the pandemic4. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Disease Models, Animal , Macaca mulatta , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Adenoviridae/genetics , Animals , Bronchoalveolar Lavage Fluid , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cytokines/immunology , Female , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/immunology , Lung/immunology , Lung/pathology , Lung/virology , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Mice , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccination , Viral Load , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
10.
Nature ; 585(7824): 268-272, 2020 09.
Article in English | MEDLINE | ID: covidwho-244486

ABSTRACT

An outbreak of coronavirus disease 2019 (COVID-19), which is caused by a novel coronavirus (named SARS-CoV-2) and has a case fatality rate of approximately 2%, started in Wuhan (China) in December 20191,2. Following an unprecedented global spread3, the World Health Organization declared COVID-19 a pandemic on 11 March 2020. Although data on COVID-19 in humans are emerging at a steady pace, some aspects of the pathogenesis of SARS-CoV-2 can be studied in detail only in animal models, in which repeated sampling and tissue collection is possible. Here we show that SARS-CoV-2 causes a respiratory disease in rhesus macaques that lasts between 8 and 16 days. Pulmonary infiltrates, which are a hallmark of COVID-19 in humans, were visible in lung radiographs. We detected high viral loads in swabs from the nose and throat of all of the macaques, as well as in bronchoalveolar lavages; in one macaque, we observed prolonged rectal shedding. Together, the rhesus macaque recapitulates the moderate disease that has been observed in the majority of human cases of COVID-19. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease, and aid in the development and testing of medical countermeasures.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Disease Models, Animal , Lung/diagnostic imaging , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiration Disorders/pathology , Respiration Disorders/virology , Animals , Body Fluids/virology , Bronchoalveolar Lavage , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Cough/complications , Female , Fever/complications , Lung/pathology , Lung/physiopathology , Lung/virology , Macaca mulatta , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Radiography , Respiration Disorders/complications , Respiration Disorders/physiopathology , SARS-CoV-2 , Time Factors , Viral Load
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