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2.
J Immunol Res ; 2022: 9764002, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35971391

RESUMO

COVID-19 has several mechanisms that can lead to lymphocyte depletion/exhaustion. The checkpoint inhibitor molecule programmed death protein 1 (PD-1) and its programmed death-ligand 1 (PDL-1) play an important role in inhibiting cellular activity as well as the depletion of these cells. In this study, we evaluated PD-1 expression in TCD4+, TCD8+, and CD19+ lymphocytes from SARS-CoV-2-infected patients. A decreased frequency of total lymphocytes and an increased PD-1 expression in TCD4+ and CD19+ lymphocytes were verified in severe/critical COVID-19 patients. In addition, we found a decreased frequency of total monocytes with an increased PD-1 expression on CD14+ monocytes in severe/critical patients in association with the time of infection. Moreover, we observed an increase in sPD-L1 circulant levels associated with the severity of the disease. Overall, these data indicate an important role of the PD-1/PDL-1 axis in COVID-19 and may provide a severity-associated biomarker and therapeutic target during SARS-CoV-2 infection.


Assuntos
Antígeno B7-H1 , COVID-19 , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , COVID-19/diagnóstico , COVID-19/patologia , Humanos , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , SARS-CoV-2 , Regulação para Cima
3.
Proc Natl Acad Sci U S A ; 119(35): e2200960119, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35951647

RESUMO

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.


Assuntos
Encéfalo , COVID-19 , Viroses do Sistema Nervoso Central , SARS-CoV-2 , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , COVID-19/complicações , COVID-19/patologia , Viroses do Sistema Nervoso Central/etiologia , Viroses do Sistema Nervoso Central/patologia , Humanos
4.
Viruses ; 14(8)2022 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-36016309

RESUMO

The coronavirus 2019 (COVID-19) disease has long-term effects, known as post-COVID conditions (PCC) or long-COVID. Post-COVID-19 syndrome is defined by signs and symptoms that occur during or after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection which persist for more than 12 weeks and cannot be supported by an alternative diagnosis. The cardiovascular damage caused by COVID-19 in the severe forms of the disease is induced by severe systemic inflammation, considered to be one of the causes of myocardial lesions, with increased levels of circulating cytokines and toxic response mediators. We have focused on conditions that can induce long-COVID-19, or multisystem inflammatory syndrome in adults or children (MIS-C/MIS-A), with an emphasis on endocrinological and metabolic disorders. Although described less frequently in children than in adults, long-COVID syndrome should not be confused with MIS-C, which is an acute condition characterized by multisystem involvement and paraclinical evidence of inflammation in a pediatric patient who tested positive for SARS-CoV-2. At the same time, we mention that the MIS-A symptoms remit within a few weeks, while the duration of long-COVID is measured in months. Long-COVID syndrome, along with its complications, MIS-A and MIS-C, represents an important challenge in the medical community. Underlying comorbidities can expose both COVID-19 adult and pediatric patients to a higher risk of negative outcomes not only during, but in the aftermath of the SARS-CoV-2 infection as well.


Assuntos
COVID-19 , Adulto , COVID-19/complicações , COVID-19/patologia , Criança , Humanos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia
5.
J Virol ; 96(17): e0096722, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-35943255

RESUMO

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.


Assuntos
COVID-19 , Quinases Semelhantes a Duplacortina , COVID-19/metabolismo , COVID-19/patologia , Calgranulina B/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Quinases Semelhantes a Duplacortina/antagonistas & inibidores , Quinases Semelhantes a Duplacortina/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucócitos Mononucleares/metabolismo , Quinolonas/farmacologia , SARS-CoV-2 , beta Catenina/metabolismo
6.
Hum Genomics ; 16(1): 33, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028902

RESUMO

BACKGROUND: The tripartite motif containing (TRIM)-22 participates in innate immune responses and exhibits antiviral activities. The present study aimed to assess of the relationship between TRIM22 single-nucleotide polymorphisms and clinical parameters with the coronavirus disease 2019 (COVID-19) infection severity. METHODS: TRIM22 polymorphisms (rs7113258, rs7935564, and rs1063303) were genotyped using TaqMan polymerase chain reaction (PCR) assay in 495 dead and 497 improved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. RESULTS: In this study, the frequencies of TRIM22 rs1063303 GG, rs7935564 GG, and rs7113258 TT were significantly higher in dead patients than in improved patients, and higher viral load with low PCR Ct value was noticed in dead patients. The multivariate logistic regression analysis revealed that the lower levels of low-density lipoprotein (LDL), cholesterol, PCR Ct value, and lower 25-hydroxyvitamin D, and also higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and TRIM22 rs1063303 GG, rs7113258 TT, and rs3824949 GG genotypes were related to the COVID-19 infection severity. CONCLUSION: Our finding proved the probable relationship between the COVID-19 infection severity with the genotypes of TRIM22 SNPs and clinical parameters. More research is required worldwide to show the association between the COVID-19 infection severity and host genetic factors.


Assuntos
COVID-19 , Antígenos de Histocompatibilidade Menor , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras , Proteínas com Motivo Tripartido , COVID-19/genética , COVID-19/patologia , Humanos , Antígenos de Histocompatibilidade Menor/genética , Nucleotídeos , Proteínas Repressoras/genética , SARS-CoV-2 , Proteínas com Motivo Tripartido/genética
7.
BMJ Case Rep ; 15(7)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902184

RESUMO

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that may be triggered by inflammation, including infection or vaccination. Since the start of the COVID-19 pandemic, several case reports were published on de novo or relapsed immune TTP (iTTP) in COVID-19-infected patients. Case reports of iTTP episodes following vaccination against COVID-19 are also emerging. We report a case of relapsed iTTP in a patient who received Moderna mRNA-1273 SARS-CoV-2 vaccine and developed concurrent severe COVID-19 infection. The patient's iTTP was successfully managed with caplacizumab, therapeutic plasma exchange and high-dose steroids. We summarise published cases of iTTP associated with COVID-19 infection or vaccination.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Vacina de mRNA-1273 contra 2019-nCoV , COVID-19/patologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Pandemias , Troca Plasmática , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Púrpura Trombocitopênica Idiopática/terapia , Púrpura Trombocitopênica Trombótica/induzido quimicamente , Púrpura Trombocitopênica Trombótica/terapia , Recidiva , SARS-CoV-2 , Vacinação/efeitos adversos
8.
Front Immunol ; 13: 934264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844548

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-ß. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-ß were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.


Assuntos
COVID-19 , Proteínas de Ligação a DNA , Fibrose Pulmonar , COVID-19/sangue , COVID-19/imunologia , COVID-19/patologia , Proteínas de Transporte , Caspase 1/imunologia , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/imunologia , Humanos , Inflamassomos/sangue , Inflamassomos/imunologia , Interferon-alfa/metabolismo , Leucócitos Mononucleares/imunologia , Fibrose Pulmonar/sangue , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , SARS-CoV-2 , Fator de Crescimento Transformador beta/metabolismo
10.
Proc Natl Acad Sci U S A ; 119(33): e2203437119, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35895716

RESUMO

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.


Assuntos
COVID-19 , Pulmão , Cadeias Leves de Miosina , SARS-CoV-2 , Índice de Gravidade de Doença , Tromboinflamação , Vasculite , COVID-19/sangue , COVID-19/complicações , COVID-19/patologia , Humanos , Leucócitos Mononucleares , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Cadeias Leves de Miosina/sangue , RNA-Seq , SARS-CoV-2/isolamento & purificação , Análise de Célula Única , Espectrometria por Raios X , Tromboinflamação/patologia , Tromboinflamação/virologia , Vasculite/patologia , Vasculite/virologia
12.
J Allergy Clin Immunol ; 150(3): 594-603.e2, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35841981

RESUMO

BACKGROUND: Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n = 29) or not admitted to an ICU (n = 29) and in age- and sex-matched healthy controls. RESULTS: We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, angiotensin-converting enzyme 2, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes. CONCLUSION: We conclude that T-cell apoptosis provoked via DNA damage due to the release of monocytic ROSs could play a major role in COVID-19 pathogenesis.


Assuntos
Angiotensina II , COVID-19 , Linfopenia , Angiotensina II/sangue , Apoptose , COVID-19/diagnóstico , COVID-19/patologia , Dano ao DNA , Humanos , Espécies Reativas de Oxigênio , SARS-CoV-2 , Linfócitos T
14.
J Cell Biol ; 221(7)2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35695891

RESUMO

Wang et al. report in this issue (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202108015) that the SARS-CoV-2 protein ORF10 increases the activity of the E3 ligase CUL2ZYG11B, leading to the degradation of multiple ciliary proteins. The resulting loss of cilia may facilitate the spread of SARS-CoV-2 in the respiratory tree.


Assuntos
COVID-19 , Cílios , Ubiquitina-Proteína Ligases , COVID-19/patologia , Proteínas de Ciclo Celular , Cílios/patologia , Proteínas Culina , Genes Virais , Humanos , Proteínas/metabolismo , SARS-CoV-2 , Ubiquitina-Proteína Ligases/metabolismo
15.
Cell Rep Med ; 3(6): 100663, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732153

RESUMO

Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1ß, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop.


Assuntos
COVID-19 , Citocinas , COVID-19/complicações , COVID-19/imunologia , COVID-19/patologia , Estudos de Coortes , Citocinas/imunologia , Progressão da Doença , Humanos , Testes Imunológicos , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Fator de Necrose Tumoral alfa/imunologia
16.
Front Immunol ; 13: 916512, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757776

RESUMO

Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.


Assuntos
COVID-19 , Glucuronidase , Glicocálix , COVID-19/metabolismo , COVID-19/patologia , Glucuronidase/metabolismo , Glicocálix/metabolismo , Glicocálix/patologia , Heparina/farmacologia , Humanos
17.
Curr Top Med Chem ; 22(16): 1307-1325, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35578850

RESUMO

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that regulates energy metabolism mainly through the pentose phosphate pathway (PPP). It is well known that this enzyme participates in the antioxidant/oxidant balance via the synthesis of energy-rich molecules: nicotinamide adenine dinucleotide phosphate reduced (NADPH), the reduced form of flavin adenine dinucleotide (FADH) and glutathione (GSH), controlling reactive oxygen species generation. Coronavirus disease 19 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health problem that has caused approximately 4.5 million deaths since December 2019. Concerning the role of G6PD in COVID-19 development, it is known from the existing literature that G6PD-deficient patients infected with SARS-CoV-2 are more susceptible to thrombosis and hemolysis, suggesting that G6PD deficiency facilitates infection by SARS-CoV-2. Concerning G6PD and neuropathology, it has been observed that deficiency of this enzyme is also present with an increase in oxidative markers. Concerning the role of G6PD and the neurological manifestations of COVID-19, it has been reported that the enzymatic deficiency in patients infected with SARSCoV- 2 exacerbates the disease, and, in some clinical reports, an increase in hemolysis and thrombosis was observed when patients were treated with hydroxychloroquine (OH-CQ), a drug with oxidative properties. In the present work, we summarize the evidence of the role of G6PD in COVID- 19 and its possible role in the generation of oxidative stress and glucose metabolism deficits, and inflammation present in this respiratory disease and its progression including neurological manifestations.


Assuntos
COVID-19 , Glucosefosfato Desidrogenase , COVID-19/metabolismo , COVID-19/patologia , Glucosefosfato Desidrogenase/metabolismo , Glutationa/metabolismo , Hemólise , Humanos , Estresse Oxidativo , SARS-CoV-2
18.
Proc Natl Acad Sci U S A ; 119(21): e2202012119, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35588457

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS­CoV-2) is a worldwide health concern, and new treatment strategies are needed. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4) and its mouse homolog, caspase-11 (CASP11), are up-regulated in SARS­CoV-2 infections and that CASP4 expression correlates with severity of SARS­CoV-2 infection in humans. SARS­CoV-2­infected Casp11−/− mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARS­CoV-2­infected WT, Casp11−/−, and Gsdmd−/− lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11−/− mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1ß, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp11−/− lungs. Additionally, Casp11−/− lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11 promotes detrimental SARS­CoV-2­induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.


Assuntos
COVID-19 , Caspases Iniciadoras/metabolismo , SARS-CoV-2 , Tromboinflamação , Animais , COVID-19/enzimologia , COVID-19/patologia , Caspases Iniciadoras/genética , Progressão da Doença , Humanos , Pulmão/patologia , Camundongos , Camundongos Knockout , Índice de Gravidade de Doença , Tromboinflamação/enzimologia , Tromboinflamação/genética
19.
Int J Antimicrob Agents ; 60(1): 106606, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35588969

RESUMO

The COVID-19 pandemic has severely impacted health systems and economies worldwide. Significant global efforts are therefore ongoing to improve vaccine efficacies, optimize vaccine deployment, and develop new antiviral therapies to combat the pandemic. Mechanistic viral dynamics and quantitative systems pharmacology models of SARS-CoV-2 infection, vaccines, immunomodulatory agents, and antiviral therapeutics have played a key role in advancing our understanding of SARS-CoV-2 pathogenesis and transmission, the interplay between innate and adaptive immunity to influence the outcomes of infection, effectiveness of treatments, mechanisms and performance of COVID-19 vaccines, and the impact of emerging SARS-CoV-2 variants. Here, we review some of the critical insights provided by these models and discuss the challenges ahead.


Assuntos
COVID-19 , Modelos Biológicos , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19 , Progressão da Doença , Humanos , Pandemias/prevenção & controle
20.
Adv Biol (Weinh) ; 6(7): e2101327, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35523737

RESUMO

Sars-Cov-2 may trigger molecular and functional alterations of cardiomyocytes (CMs) of the heart due to the presence of receptor angiotensin-converting enzyme 2 (ACE2) of the host cells. While the endocytic itinerary of the virus via cleavage of the spike protein of Sars-Cov-2 is well understood, the role of the remaining part of the spike protein subunit and ACE2 complex is still elusive. Herein, the possible effects of this complex are investigated by using synthetic spike proteins of Sars-Cov-2, human-induced pluripotent stem cells (hiPSC), and a culture device made of an arrayed monolayer of cross-linked nanofibers. hiPSCs are first differentiated into CMs that form cardiac tissue-like constructs with regular beating and expression of both ACE2 and gap junction protein Connexin 43. When incubated with the spike proteins, the hiPSC-CMs undergo a rhythmic fluctuation with overstretched sarcomere structures and dispersed gap junction proteins. When incubated with the spike proteins and supplementary angiotensin II, the damage of the spike protein on hiPSC-CMs is enhanced due to downregulated ACE2, chromatin margination, altered Connexin 43 expression, sarcomere disruption, and beating break. This discovery may imply latent effects of the spike proteins on the heart.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Miócitos Cardíacos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/patologia , COVID-19/fisiopatologia , Conexina 43/metabolismo , Técnicas de Cultura , Humanos , Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
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