Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Viruses ; 14(4)2022 04 17.
Article in English | MEDLINE | ID: covidwho-1792411

ABSTRACT

Combined in silico, in vitro, and in vivo comparative studies between isogenic-recombinant Mouse-Hepatitis-Virus-RSA59 and its proline deletion mutant, revealed a remarkable contribution of centrally located two consecutive prolines (PP) from Spike protein fusion peptide (FP) in enhancing virus fusogenic and hepato-neuropathogenic potential. To deepen our understanding of the underlying factors, we extend our studies to a non-fusogenic parental virus strain RSMHV2 (P) with a single proline in the FP and its proline inserted mutant, RSMHV2 (PP). Comparative in vitro and in vivo studies between virus strains RSA59(PP), RSMHV2 (P), and RSMHV2 (PP) in the FP demonstrate that the insertion of one proline significantly resulted in enhancing the virus fusogenicity, spread, and consecutive neuropathogenesis. Computational studies suggest that the central PP in Spike FP induces a locally ordered, compact, and rigid structure of the Spike protein in RSMHV2 (PP) compared to RSMHV2 (P), but globally the Spike S2-domain is akin to the parental strain RSA59(PP), the latter being the most flexible showing two potential wells in the energy landscape as observed from the molecular dynamics studies. The critical location of two central prolines of the FP is essential for fusogenicity and pathogenesis making it a potential site for designing antiviral.


Subject(s)
Demyelinating Diseases , Spike Glycoprotein, Coronavirus , Animals , Mice , Peptides/metabolism , Proline , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism
2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321649

ABSTRACT

Global lockdowns in response to the COVID-19 pandemic have led to changes in the anthropogenic activities resulting in perceivable air quality improvements. Although several recent studies have analyzed these changes over different regions of the globe, these analyses have been constrained due to the usage of station-based data which is mostly limited upto the metropolitan cities. Also, the quantifiable changes have been reported only for the developed and developing regions leaving the poor economies (e.g. Africa) due to the shortage of in-situ data. Using a comprehensive set of high spatiotemporal resolution satellites and merged products of air pollutants, we analyze the air quality across the globe and quantify the improvement resulting from the suppressed anthropogenic activity during the lockdowns. In particular, we focus on megacities, capitals and cities with high standards of living to make the quantitative assessment. Our results offer valuable insights into the spatial distribution of changes in the air pollutants due to COVID-19 enforced lockdowns. Statistically significant reductions are observed over megacities with mean reduction by 19.74%, 7.38% and 49.9% in nitrogen dioxide (NO2), aerosol optical depth (AOD) and PM 2.5 concentrations. Google Earth Engine empowered cloud computing based remote sensing is used and the results provide a testbed for climate sensitivity experiments and validation of chemistry-climate models. Additionally, Google Earth Engine based apps have been developed to visualize the changes in a real-time fashion.

3.
Cell Rep Med ; 3(3): 100549, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1677212

ABSTRACT

The COVID-19 pandemic has seen clinical development and use of antiviral therapies at an unprecedented speed. Antiviral therapies have greatly improved the clinical outcome in COVID-19 patients, especially when administered early after diagnosis. Here, we discuss the successes and challenges of COVID-19 antiviral therapies and lessons for future pandemics.


Subject(s)
COVID-19 , Influenza, Human , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Forecasting , Humans , Influenza, Human/drug therapy , Pandemics
4.
Antiviral Res ; 198: 105246, 2022 02.
Article in English | MEDLINE | ID: covidwho-1639070

ABSTRACT

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung Diseases, Interstitial/prevention & control , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Administration, Cutaneous , Alanine/administration & dosage , Alanine/pharmacokinetics , Alanine/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Disease Models, Animal , Female , Lung/pathology , Lung/virology , Macaca mulatta , Male , Viral Load/drug effects , Virus Replication/drug effects
5.
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
6.
Sci Adv ; 7(43): eabj3627, 2021 Oct 22.
Article in English | MEDLINE | ID: covidwho-1483968

ABSTRACT

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors. Here, we compared variants of concern (VOC) B.1.1.7 and B.1.351 to a recent B.1 SARS-CoV-2 isolate containing the D614G spike substitution in the rhesus macaque model. B.1.1.7 behaved similarly to D614G with respect to clinical disease and replication in the respiratory tract. Inoculation with B.1.351 resulted in lower clinical scores, lower lung virus titers, and less severe lung lesions. In bronchoalveolar lavages, cytokines and chemokines were up-regulated on day 4 in animals inoculated with D614G and B.1.1.7 but not with B.1.351. In nasal samples, cytokines and chemokines were up-regulated only in the B.1.1.7-inoculated animals. Together, our study suggests that circulation under diverse evolutionary pressures favors transmissibility and immune evasion rather than increased pathogenicity.

7.
J Biol Chem ; 295(20): 6926-6935, 2020 05 15.
Article in English | MEDLINE | ID: covidwho-830746

ABSTRACT

Mouse hepatitis virus (MHV; murine coronavirus) causes meningoencephalitis, myelitis, and optic neuritis followed by axonal loss and demyelination. This murine virus is used as a common model to study acute and chronic virus-induced demyelination in the central nervous system. Studies with recombinant MHV strains that differ in the gene encoding the spike protein have demonstrated that the spike has a role in MHV pathogenesis and retrograde axonal transport. Fusion peptides (FPs) in the spike protein play a key role in MHV pathogenesis. In a previous study of the effect of deleting a single proline residue in the FP of a demyelinating MHV strain, we found that two central, consecutive prolines are important for cell-cell fusion and pathogenesis. The dihedral fluctuation of the FP was shown to be repressed whenever two consecutive prolines were present, in contrast to the presence of a single proline in the chain. Using this proline-deleted MHV strain, here we investigated whether intracranial injection of this strain can induce optic neuritis by retrograde axonal transport from the brain to the retina through the optic nerve. We observed that the proline-deleted recombinant MHV strain is restricted to the optic nerve, is unable to translocate to the retina, and causes only minimal demyelination and no neuronal death. We conclude that an intact proline dyad in the FP of the recombinant demyelinating MHV strain plays a crucial role in translocation of the virus through axons and subsequent neurodegeneration.


Subject(s)
Axonal Transport/genetics , Murine hepatitis virus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Animals , Axonal Transport/physiology , Axons/metabolism , Axons/virology , Brain/metabolism , Coronavirus Infections/pathology , Demyelinating Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/metabolism , Optic Nerve/metabolism , Optic Nerve/virology , Peptides/metabolism , Proline/metabolism , Sequence Deletion/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Envelope Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL