RESUMEN
BACKGROUND: SARS-CoV-2 remains rapidly evolving, and many biologically important genomic substitutions/indels have characterised novel SARS-CoV-2 lineages, which have emerged during successive global waves of the pandemic. Worldwide genomic sequencing has been able to monitor these waves, track transmission clusters, and examine viral evolution in real time to help inform healthcare policy. One school of thought is that an apparent greater than average divergence in an emerging lineage from contemporary variants may require persistent infection, for example in an immunocompromised host. Due to the nature of the COVID-19 pandemic and sampling, there were few studies that examined the evolutionary trajectory of SARS-CoV-2 in healthy individuals. METHODS: We investigated viral evolutionary trends and participant symptomatology within a cluster of 16 SARS-CoV-2 infected, immunocompetent individuals with no co-morbidities in a closed transmission chain. Longitudinal nasopharyngeal swab sampling allowed characterisation of SARS-CoV-2 intra-host variation over time at both the dominant and minor genomic variant levels through Nimagen-Illumina sequencing. RESULTS: A change in viral lineage assignment was observed in individual infections; however, there was only one indel and no evidence of recombination over the period of an acute infection. Minor and dominant genomic modifications varied between participants, with some minor genomic modifications increasing in abundance to become the dominant viral sequence during infection. CONCLUSIONS: Data from this cohort of SARS-CoV-2-infected participants demonstrated that long-term persistent infection in an immunocompromised host was not necessarily a prerequisite for generating a greater than average frequency of amino acid substitutions. Amino acid substitutions at both the dominant and minor genomic sequence level were observed in immunocompetent individuals during infection showing that viral lineage changes can occur generating viral diversity.
Asunto(s)
COVID-19 , Genoma Viral , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/transmisión , COVID-19/virología , COVID-19/genética , Masculino , Adulto , Femenino , Persona de Mediana Edad , Variación Genética , Inmunocompetencia , Evolución Molecular , Filogenia , AncianoRESUMEN
There is an enduring requirement to develop animal models of COVID-19 to assess the efficacy of vaccines and therapeutics that can be used to treat the disease in humans. In this study, six marmosets were exposed to a small particle aerosol (1-3 µm) of SARS-CoV-2 VIC01 that delivered the virus directly to the lower respiratory tract. Following the challenge, marmosets did not develop clinical signs, although a disruption to the normal diurnal temperature rhythm was observed in three out of six animals. Early weight loss and changes to respiratory pattern and activity were also observed, yet there was limited evidence of viral replication or lung pathology associated with infection. There was a robust innate immunological response to infection, which included an early increase in circulating neutrophils and monocytes and a reduction in the proportion of circulating T-cells. Expression of the ACE2 receptor in respiratory tissues was almost absent, but there was ubiquitous expression of TMPRSS2. The results of this study indicate that exposure of marmosets to high concentrations of aerosolised SARS-CoV-2 did not result in the development of clear, reproducible signs of COVID-19.
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COVID-19 , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Animales , Callithrix/metabolismo , Humanos , Peptidil-Dipeptidasa A/metabolismoRESUMEN
Two strains of Middle East respiratory syndrome coronavirus (MERS-CoV), England 1 and Erasmus Medical Centre/2012 (EMC/2012), were used to challenge common marmosets (Callithrix jacchus) by three routes of infection: aerosol, oral, and intranasal. Animals challenged by the intranasal and aerosol routes presented with mild, transient disease, while those challenged by the oral route presented with a subclinical immunological response. Animals challenged with MERS-CoV strain EMC/2012 by the aerosol route responded with primary and/or secondary pyrexia. Marmosets had minimal to mild multifocal interstitial pneumonia, with the greatest relative severity being observed in animals challenged by the aerosol route. Viable virus was isolated from the host in throat swabs and lung tissue. The transient disease described is consistent with a successful host response and was characterized by the upregulation of macrophage and neutrophil function observed in all animals at the time of euthanasia. IMPORTANCE Middle East respiratory syndrome is caused by a human coronavirus, MERS-CoV, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Humans typically exhibit fever, cough, shortness of breath, gastrointestinal issues, and breathing difficulties, which can lead to pneumonia and/or renal complications. This emerging disease resulted in the first human lethal cases in 2012 and has a case fatality rate of approximately 36%. Consequently, there is a need for medical countermeasures and appropriate animal models for their assessment. This work has demonstrated the requirement for higher concentrations of virus to cause overt disease. Challenge by the aerosol, intranasal, and oral routes resulted in no or mild disease, but all animals had an immunological response. This shows that an appropriate early immunological response is able to control the disease.
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COVID-19/metabolismo , Modelos Animales de Enfermedad , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , SARS-CoV-2/metabolismo , Animales , Callithrix , HumanosRESUMEN
With the rise of antimicrobial resistance, novel ways to treat bacterial infections are required and the use of predatory bacteria may be one such approach. Bdellovibrio species have been shown in vitro to predate on a wide range of other Gram-negative bacteria, including CDC category A/B pathogens such as Yersinia pestis. The data reported here show that treatment of SKH-1 mice with Bdellovibrio bacteriovorus HD100 provided significant protection from a lethal challenge of Yersinia pestis CO92. This is the first report of protection conferred by predation in vivo against a systemic pathogen challenge. However, this protective effect was not observed in a preliminary study with Balb/c mice. Therefore the effects of the predatory bacteria are complex and may be dependent on immune status/genetics of the host. Overall, predatory bacteria may have utility as a therapeutic modality but further work is required to understand the predator-host interaction.