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2.
Protein Cell ; 13(12): 920-939, 2022 12.
Article in English | MEDLINE | ID: covidwho-1773029

ABSTRACT

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19/genetics , Macaca mulatta , SARS-CoV-2/genetics , Transcriptome
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324533

ABSTRACT

SARS-CoV-2 infection causes complicated clinic manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various tissues/organs examined, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Neuronal receptor NRP1 expression showed a significant induction by SARS-CoV-2 in cerebral cortex, which might be responsible for a higher infectivity and consequent inflammatory response. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

4.
Cell Mol Immunol ; 19(2): 210-221, 2022 02.
Article in English | MEDLINE | ID: covidwho-1608557

ABSTRACT

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.


Subject(s)
Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cell-Derived Microparticles/metabolism , Cholesterol/metabolism , Endosomes/chemistry , Macrophages, Alveolar/metabolism , SARS-CoV-2/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Female , Humans , Hydrogen-Ion Concentration , Lysosomes/chemistry , Mice , Mice, Inbred ICR , Mice, Transgenic , Oxidation-Reduction , RAW 264.7 Cells , Treatment Outcome , Vero Cells
8.
Cell Discov ; 7(1): 24, 2021 Apr 13.
Article in English | MEDLINE | ID: covidwho-1182824

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.

10.
Cell Res ; 30(12): 1078-1087, 2020 12.
Article in English | MEDLINE | ID: covidwho-912896

ABSTRACT

Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-ß or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.


Subject(s)
Interferons/metabolism , Mucus/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Animals , COVID-19/pathology , COVID-19/virology , Cell Line , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Hypoxia , Interferon-beta/pharmacology , Interferon-gamma/pharmacology , Lung/metabolism , Lung/pathology , Macaca , Mice , Mice, Inbred ICR , Mice, Transgenic , Mucins/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Signal Transduction , Up-Regulation/drug effects
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