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1.
Frontiers in public health ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1877034
3.
Viruses ; 14(3)2022 03 06.
Article in English | MEDLINE | ID: covidwho-1786061

ABSTRACT

The emergence of SARS-CoV-2 in the human population and the resulting COVID-19 pandemic have led to the development of various diagnostic tests. The OraSure InteliSwab™ COVID-19 Rapid Test is a recently developed and FDA emergency use-authorized rapid antigen-detecting test that functions as a lateral flow device targeting the nucleocapsid protein. Due to SARS-CoV-2 evolution, there is a need to evaluate the sensitivity of rapid antigen-detecting tests for new variants, especially variants of concern such as Omicron. In this study, the sensitivity of the OraSure InteliSwab™ Test was investigated using cultured strains of the known variants of concern (VOCs, Alpha, Beta, Gamma, Delta, and Omicron) and the ancestral lineage (lineage A). Based on dilution series in cell culture medium, an approximate limit of detection for each variant was determined. The OraSure InteliSwab™ Test showed an overall comparable performance using recombinant nucleocapsid protein and different cultured variants, with recorded limits of detection ranging between 3.77 × 105 and 9.13 × 105 RNA copies/mL. Finally, the sensitivity was evaluated using oropharyngeal swabs from Syrian golden hamsters inoculated with the six VOCs. Ultimately, the OraSure InteliSwab™ COVID-19 Rapid Test showed no decrease in sensitivity between the ancestral SARS-CoV-2 strain and any VOCs including Omicron.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Humans , Nucleocapsid Proteins/genetics , Pandemics , SARS-CoV-2/genetics
4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331333

ABSTRACT

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

5.
PLoS Pathog ; 18(1): e1010161, 2022 01.
Article in English | MEDLINE | ID: covidwho-1703195

ABSTRACT

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.


Subject(s)
COVID-19/etiology , Disease Models, Animal , SARS-CoV-2 , Age Factors , Animals , COVID-19/prevention & control , COVID-19/therapy , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Comorbidity , Humans , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
6.
Microorganisms ; 10(2)2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1706054

ABSTRACT

As the COVID-19 pandemic moves into its third year, there remains a need for additional animal models better recapitulating severe COVID to study SARS-CoV-2 pathogenesis and develop countermeasures, especially treatment options. Pigs are known intermediate hosts for many viruses with zoonotic potential and are susceptible to infection with alpha, beta and delta genera of coronaviruses. Herein, we infected young (3 weeks of age) pigs with SARS-CoV-2 using a combination of respiratory and parenteral inoculation routes. Pigs did not develop clinical disease, nor macroscopic or microscopic pathologic lesions upon SARS-CoV-2 infection. Despite occasional low levels of SARS-CoV-2 genomic RNA in the respiratory tract, subgenomic RNA and infectious virus were never found, and SARS-CoV-2-specific adaptive immune responses were not detectable over the 13-day study period. We concluded that pigs are not susceptible to productive SARS-CoV-2 infection and do not serve as a SARS-CoV-2 reservoir for zoonotic transmission.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-319258

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 increased trend of systemic IL-10 and IL-6, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, 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.Funding Information: This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).Declaration of Interests: The authors declare no competing financial interests.Ethics Approval Statement: Approval of animal experiments was obtained from the Institutional Animal Care and Use Committee of the Rocky Mountain Laboratories. Performance of experiments was done following the guidelines and basic principles in the United States Public Health Service Policy on Humane Care and Use of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals. Work with infectious SARS-CoV-2 strains under BSL3 conditions was approved by the Institutional Biosafety Committee (IBC). Inactivation and removal of samples from high containment was performed per IBC-approved standard operating procedures.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314818

ABSTRACT

Sensitive and specific SARS-CoV-2 antibody assays remain critical for community and hospital-based SARS-CoV-2 surveillance. Here, we developed and applied a multiplex microsphere-based immunoassay (MMIA) for COVD-19 antibody studies that incorporates spike protein trimers of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and the seasonal human betacoronaviruses, HCoV-HKU1 and HCoV-OC43, that enables measurement of off-target pre-existing cross-reactive antibodies. The MMIA performances characteristics are: 98% sensitive and 100% specific for human subject samples collected as early as 10 days from symptom onset. The MMIA permitted the simultaneous identification of SARS-CoV-2 seroconversion and the induction of SARS-CoV-2 IgG antibody cross reactions to SARS-CoV-1 and MERS-CoV. Further, synchronous increases of HCoV-OC43 IgG antibody levels was detected with SARS-CoV-2 seroconversion in a subset of subjects for whom early infection sera were available prior to their SARS-CoV-2 seroconversion, suggestive of an HCoV-OC43 memory response triggered by SARS-CoV-2 infection.

9.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328855

ABSTRACT

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus–vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 was shown to have 74% vaccine efficacy (VE) against symptomatic disease in clinical trials and over 2.5 billion doses of vaccine have been released for worldwide use. However, SARS-CoV-2 continues to circulate and consequently, variants of concern (VoCs) have been detected, with substitutions in the S protein that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial over boosting with vaccines encoding the ancestral S protein, even though current real-world data is suggesting good efficacy against hospitalization and death following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluated the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. We then investigated the efficacy of a single dose of AZD2816 or AZD1222 against the Omicron VoC. As seen previously, minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 5 days post inoculation, in contrast to lungs of control animals. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.

10.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327368

ABSTRACT

The emergence of SARS-CoV-2 in the human population and the resulting COVID-19 pandemic has led to the development of various diagnostic tests. The OraSure InteliSwab ® COVID-19 Rapid Test is a recently developed and FDA emergency use authorized rapid antigen-detecting test that functions as a lateral flow device targeting the nucleocapsid protein. Due to SARS-CoV-2 evolution, there is a need to evaluate the sensitivity of rapid antigen-detecting tests for new variants, especially variants of concern like Omicron. In this study, the sensitivity of the OraSure InteliSwab ® Test was investigated using cultured strains of the known variants of concern (VOCs, Alpha, Beta, Gamma, Delta, and Omicron) and the ancestral lineage (lineage A). Based on dilution series in cell culture medium, an approximate limit of detection for each variant was determined. The OraSure InteliSwab ® Test showed an overall comparable performance using recombinant nucleocapsid protein and different cultured variants with recorded limits of detection ranging between 3.77 × 10 5 and 9.13 × 10 5 RNA copies/mL. Finally, the sensitivity was evaluated using oropharyngeal swabs from Syrian golden hamsters inoculated with the 6 VOCs. Ultimately, the OraSure InteliSwab ® COVID-19 Rapid Test showed no decrease in sensitivity between the ancestral SARS-CoV-2 strain and any VOCs including Omicron.

11.
PLoS Pathog ; 18(2): e1009914, 2022 02.
Article in English | MEDLINE | ID: covidwho-1686113

ABSTRACT

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel SARS-CoV-2 variant designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and it was shown to have enhanced infectivity in vitro and decreased antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both variants exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most marked body weight loss among the 3 variants. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three variants. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the oropharynx but not in the lungs. In multi-virus in-vivo competition experiments, we found that B.1. (614G), epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the nasal cavity, B.1. (614G), gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) and WA-1 variants in hamsters. These results demonstrate enhanced virulence and high relative oropharyngeal replication of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) variant.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , Animals , COVID-19/pathology , Disease Models, Animal , Female , Humans , Lung/pathology , Lung/virology , Male , Mesocricetus , Mutation , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virulence
13.
Life Sci Alliance ; 5(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1637974

ABSTRACT

Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, we used the rhesus macaque model of SARS-CoV-2 infection. Eight older and eight younger macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at predefined time points in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication were limited. Transcriptional signatures of inflammation-associated genes in bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both cohorts. However, age-specific divergence of immune responses emerged during the post-acute phase. Older animals exhibited sustained local inflammatory innate responses, whereas local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, and persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling suggests that age may delay or impair antiviral cellular immune responses and delay efficient return to immune homeostasis.


Subject(s)
Aging/immunology , COVID-19/immunology , COVID-19/veterinary , SARS-CoV-2/immunology , Acute Disease , Animals , Antibody Formation/immunology , Bronchoalveolar Lavage Fluid , COVID-19/complications , COVID-19/genetics , Cytokines/blood , Gene Expression Regulation , Gene Regulatory Networks , Genomics , Immunity, Cellular/genetics , Immunomodulation , Inflammation/complications , Inflammation/pathology , Lung/immunology , Lung/pathology , Lung/virology , Lymphoid Tissue/pathology , Macaca mulatta/immunology , Macaca mulatta/virology , Models, Biological , Single-Cell Analysis , T-Lymphocytes/immunology , Transcription, Genetic
14.
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
15.
Vet Pathol ; 59(4): 673-680, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1582697

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an emergent, amphixenotic infection that resulted in a pandemic declaration in March 2020. A rapid search for appropriate animal models of this newly emergent viral respiratory disease focused initially on traditional nonhuman primate research species. Nonhuman primate models have previously been shown to be valuable in evaluation of emerging respiratory coronaviruses with pandemic potential (ie, SARS-CoV and Middle East respiratory syndrome coronavirus). In this article, we review the pulmonary histopathologic characteristics and immunohistochemical evaluation of experimental SARS-CoV-2 infection in the rhesus macaque, pigtail macaque, African green monkey, and squirrel monkey. Our results indicate that all evaluated nonhuman primate species developed variably severe histopathologic changes typical of coronavirus respiratory disease characterized by interstitial pneumonia with or without syncytial cell formation, alveolar fibrin, and pulmonary edema that progressed to type II pneumocyte hyperplasia. Lesion distribution was multifocal, frequently subpleural, and often more severe in lower lung lobes. However, squirrel monkeys showed the least severe and least consistent lesions of the evaluated nonhuman primates. Additionally, our results highlight the disparate physical relationship between viral antigen and foci of pulmonary lesions. While classic respiratory coronaviral lesions were observed in the lungs of all nonhuman primates evaluated, none of the primates exhibited severe lesions or evidence of diffuse alveolar damage and therefore are unlikely to represent the severe form of SARS-CoV-2 infection observed in fatal human cases.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19/veterinary , Chlorocebus aethiops , Lung/pathology , Macaca mulatta , Pandemics/veterinary
16.
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
17.
Proc Natl Acad Sci U S A ; 118(50)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1560743

ABSTRACT

Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts toward control of COVID-19. We developed a live intranasal vector vaccine for infants and children against COVID-19 based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) that express the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as B/HPIV3 in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2-neutralizing antibodies (12-fold higher), serum IgA and IgG to SARS-CoV-2 S protein (5-fold and 13-fold), and IgG to the receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with 104.5 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 106.6 TCID50/g in lungs and 107 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P-immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S and B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , SARS-CoV-2/immunology , Administration, Intranasal , Animals , Antibodies, Viral/blood , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Cricetinae , Genetic Vectors , Immunization , Parainfluenza Virus 3, Bovine/genetics , Parainfluenza Virus 3, Human/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
18.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294709

ABSTRACT

We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observed a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 did not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals did not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus was detected in lungs of vaccinated animals. Histopathological evaluation showed extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.

19.
Emerg Infect Dis ; 27(12): 3052-3062, 2021 12.
Article in English | MEDLINE | ID: covidwho-1528794

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) infects humans and dromedary camels and is responsible for an ongoing outbreak of severe respiratory illness in humans in the Middle East. Although some mutations found in camel-derived MERS-CoV strains have been characterized, most natural variation found across MERS-CoV isolates remains unstudied. We report on the environmental stability, replication kinetics, and pathogenicity of several diverse isolates of MERS-CoV, as well as isolates of severe acute respiratory syndrome coronavirus 2, to serve as a basis of comparison with other stability studies. Although most MERS-CoV isolates had similar stability and pathogenicity in our experiments, the camel-derived isolate C/KSA/13 had reduced surface stability, and another camel isolate, C/BF/15, had reduced pathogenicity in a small animal model. These results suggest that although betacoronaviruses might have similar environmental stability profiles, individual variation can influence this phenotype, underscoring the need for continual global viral surveillance.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Aerosols , Animals , Camelus , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , SARS-CoV-2 , Virulence , Zoonoses
20.
[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.

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