RESUMO
To improve the prognosis of patients suffering from pulmonary diseases, such as lung cancer, early diagnosis and treatment are crucial. The analysis of CT images is invaluable for diagnosis, whereas high quality segmentation of the airway tree are required for intervention planning and live guidance during bronchoscopy. Recently, the Multi-domain Airway Tree Modeling (ATM'22) challenge released a large dataset, both enabling training of deep-learning based models and bringing substantial improvement of the state-of-the-art for the airway segmentation task. The ATM'22 dataset includes a large group of COVID'19 patients and a range of other lung diseases, however, relatively few patients with severe pathologies affecting the airway tree anatomy was found. In this study, we introduce a new public benchmark dataset (AeroPath), consisting of 27 CT images from patients with pathologies ranging from emphysema to large tumors, with corresponding trachea and bronchi annotations. Second, we present a multiscale fusion design for automatic airway segmentation. Models were trained on the ATM'22 dataset, tested on the AeroPath dataset, and further evaluated against competitive open-source methods. The same performance metrics as used in the ATM'22 challenge were used to benchmark the different considered approaches. Lastly, an open web application is developed, to easily test the proposed model on new data. The results demonstrated that our proposed architecture predicted topologically correct segmentations for all the patients included in the AeroPath dataset. The proposed method is robust and able to handle various anomalies, down to at least the fifth airway generation. In addition, the AeroPath dataset, featuring patients with challenging pathologies, will contribute to development of new state-of-the-art methods. The AeroPath dataset and the web application are made openly available.
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Benchmarking , COVID-19 , Tomografia Computadorizada por Raios X , Humanos , COVID-19/diagnóstico por imagem , COVID-19/patologia , Tomografia Computadorizada por Raios X/métodos , Aprendizado Profundo , SARS-CoV-2 , Pulmão/diagnóstico por imagem , Pulmão/patologia , Processamento de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologiaAssuntos
COVID-19 , Morte Celular , SARS-CoV-2 , COVID-19/virologia , COVID-19/patologia , Humanos , SARS-CoV-2/patogenicidadeRESUMO
BACKGROUND: While COVID-19 has been controlled and deaths have decreased, the long-term consequences of COVID-19 remain a challenge we face today. This study was conducted to determine the relationship between the apoptosis of lymphocyte cells with DNA damage and oxidative stress and the therapeutic and clinical outcomes of elderly patients with COVID-19. METHODS: This study was conducted from April 2020 to May 2021 (the period of severe attacks of the epidemic peak of COVID-19) and September 2022 (the post-COVID-19 period). The study groups included elderly patients with COVID-19 hospitalized in the ICU and normal wards of the hospital as well as elderly patients with influenza. A polymerase chain reaction was used to check the validity of the studied diseases. The Annexin V/Propidium Iodide method was used to evaluate the level of apoptosis. Genotoxic effects and DNA damage were assessed by the comet assay method. Total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase activity (MPO) were measured by photometric methods. RESULTS: The highest level of apoptosis in peripheral blood lymphocytes and the highest level of DNA damage were observed at both times in the intubated-ICU and non-intubated-ICU groups. In all groups, there was a significant increase in peripheral blood lymphocyte apoptosis levels and DNA damage levels compared to the healthy control group (p < 0.01). The level of apoptosis and DNA damage decreased significantly in the post-COVID-19 period (p < 0.01). In the investigation of oxidative stress biomarkers, the oxidative stress index, including TOS and MPO levels, increased in patients (p < 0.01), and the TAS level decreased (p < 0.01). CONCLUSION: It shows that the apoptosis of lymphocyte cells, DNA damage, and oxidative stress can be effective in prognostic decisions and is a suitable predictor for diagnosing the condition of patients with viral infections such as COVID-19 and influenza.
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Apoptose , COVID-19 , Dano ao DNA , Linfócitos , Estresse Oxidativo , SARS-CoV-2 , Humanos , COVID-19/patologia , COVID-19/terapia , Idoso , Masculino , Feminino , Idoso de 80 Anos ou mais , Antioxidantes/metabolismoRESUMO
To investigate if retinal thickness has predictive utility in COVID-19 outcomes by evaluating the statistical association between retinal thickness using OCT and of COVID-19-related mortality. Secondary outcomes included associations between retinal thickness and length of stay (LoS) in hospital. In this retrospective cohort study, OCT scans from 230 COVID-19 patients admitted to the Intensive Care Unit (ITU) were compared with age and gender-matched patients with pneumonia from before March 2020. Total retinal, GCL + IPL, and RNFL thicknesses were recorded, and analysed with systemic measures collected at the time of admission and mortality outcomes, using linear regression models, Pearson's R correlation, and Principal Component Analysis. Retinal thickness was significantly associated with all-time mortality on follow up in the COVID-19 group (p = 0.015), but not 28-day mortality (p = 0.151). Retinal and GCL + IPL layer thicknesses were both significantly associated with LoS in hospital for COVID-19 patients (p = 0.006 for both), but not for patients with pneumonia (p = 0.706 and 0.989 respectively). RNFL thickness was not associated with LoS in either group (COVID-19 p = 0.097, pneumonia p = 0.692). Retinal thickness associated with LoS in hospital and long-term mortality in COVID-19 patients, suggesting that retinal structure could be a surrogate marker for frailty and predictor of disease severity in this group of patients, but not in patients with pneumonia from other causes.
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COVID-19 , Unidades de Terapia Intensiva , Retina , Tomografia de Coerência Óptica , Humanos , COVID-19/mortalidade , COVID-19/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Retina/patologia , Retina/diagnóstico por imagem , Idoso , Tomografia de Coerência Óptica/métodos , Tempo de Internação , SARS-CoV-2/isolamento & purificação , HospitalizaçãoRESUMO
Introduction: Pulmonary fibrosis (PF) encompasses a spectrum of lung conditions characterized by the abnormal accumulation of scar tissue in the lungs, leading to impaired respiratory function. Various conditions can result in severe PF, among which viral infections have emerged as significant triggers. In addition to viral infections, exposure to toxic substances such as paraquat represents another significant risk factor for PF. Therefore, this study aimed to explore the dissimilarities and similarities between PF triggered by viral infections and chemical toxicants, using the mechanism of PF in IPF as a reference. Methods: Data-independent acquisition proteomics technology was employed to identify COVID-19 and paraquat-induced PF from the autopsy of lung tissue samples obtained from individuals who died due to PF. Bioinformatics was employed for differential protein analysis, and selected indicators were validated on pathological sections. Results: Our results showed that the differential proteins associated with the two causes of PF were enriched in similar lung fibrosis-related signaling pathways, such as the Wnt signaling pathway. However, differences were observed in proteins such as CACYBP, we verified the consistency of the results with proteomics using the IHC approach. Conclusion: This study illuminates distinct protein-level differences by investigating pulmonary fibrosis pathways in severe COVID-19 and paraquat poisoning. Although both conditions activate lung-protective and repair pathways, COVID-19 shows limited phosphorylation-independent ubiquitination of ß-catenin compared to paraquat toxicity. These findings shed light on potential therapeutic targets for PF induced via diverse factors.
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COVID-19 , Pulmão , Paraquat , Proteômica , Fibrose Pulmonar , SARS-CoV-2 , Humanos , Paraquat/intoxicação , COVID-19/metabolismo , COVID-19/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , Fibrose Pulmonar/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Feminino , IdosoRESUMO
BACKGROUND: CT-scan and inflammatory and coagulation biomarkers could help in prognostication of COVID-19 in patients on ICU admission. OBJECTIVE: The objectives of this study were to measure the prognostic value of the extent of lung parenchymal lesions on computed tomography (CT) and of several coagulation and inflammatory biomarkers, and to explore the characteristics of the patients depending on the extent of lung parenchymal lesions. DESIGN: Retrospective monocentric observational study achieved on a dataset collected prospectively. SETTING: Medical ICU of the university hospital of Clermont-Ferrand, France. PATIENTS: All consecutive adult patients aged ≥18 years admitted between 20 March, 2020 and 31 August, 2021 for COVID-19 pneumonia. INTERVENTIONS: Characteristics at baseline and during ICU stay, and outcomes at day 60 were recorded. The extent of lung parenchyma lesions observed on the chest CT performed on admission was established by artificial intelligence software. MEASUREMENTS: Several clinical characteristics and laboratory features were collected on admission including plasma interleukin-6, HLA-DR monocytic-expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day-60 mortality were investigated by uni- and multivariate survival analyses. RESULTS: 270 patients were included. Inflammation biomarkers including the levels of neutrophils, CRP, ferritin and Il10 were the indices the most associated with the severity of the extent of the lung lesions. Patients with more extensive lung parenchymal lesions (≥ 75%) on admission had higher CRP serum levels. The extent of lung parenchymal lesions was associated with a decrease in the PaO2/FiO2 ratio(p<0.01), fewer ventilatory-free days (p = 0.03), and a higher death rate at day 60(p = 0.01). Extent of the lesion of more than 75% was independently associated with day-60 mortality (aHR = 1.72[1.06; 2.78], p = 0.03). The prediction of death at day 60 was improved when considering simultaneously biological and radiological markers obtained on ICU admission (AUC = 0.78). CONCLUSIONS: The extent of lung parenchyma lesions on CT was associated with inflammation, and the combination of coagulation and inflammatory biomarkers and the extent of the lesions predicted the poorest outcomes.
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COVID-19 , Unidades de Terapia Intensiva , Pulmão , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Humanos , COVID-19/diagnóstico por imagem , COVID-19/sangue , COVID-19/mortalidade , COVID-19/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Pulmão/diagnóstico por imagem , Pulmão/patologia , Estudos Retrospectivos , Prognóstico , Biomarcadores/sangue , Adulto , França/epidemiologia , Interleucina-6/sangue , Idoso de 80 Anos ou maisRESUMO
Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3-/-; 2. C7-/-; and 3. Cd59ab-/-) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3-/-) and MAC formation (in C3-/-. C7-/-, and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation (Cd59ab-/-) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3-/-, C7-/- mice, and Cd59ab-/- mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19.
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Antígenos CD59 , COVID-19 , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento , Camundongos Knockout , SARS-CoV-2 , Animais , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Ativação do Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Camundongos , SARS-CoV-2/imunologia , Antígenos CD59/metabolismo , Antígenos CD59/genética , Antígenos CD59/imunologia , Complemento C3/imunologia , Complemento C3/metabolismo , Complemento C3/genética , Camundongos Endogâmicos C57BL , Humanos , Complemento C5/imunologia , Complemento C5/metabolismo , Complemento C5/antagonistas & inibidores , Modelos Animais de DoençasRESUMO
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a deadly pulmonary disease with impaired immunological response that causes significant tissue damage and organ failure. Postmortem examination of the lung is a useful tool for understanding the immunopathogenesis of this virus. Lung autopsy samples from seven dead SARS-CoV-2 patients were obtained and evaluated using hematoxylin and eosin stain to analyze the histopathological changes in those samples, on the other hand, Immunohistochemical (IHC) staining was used for detection of CD21, CD1a, CR1 (CD35), CD68, Myeloperoxidase (MPO), CD15, CD56, CD3, CD20, CD4, and CD8 cells markers. Histopathological examination revealed diffuse alveolar damage with extensive parenchymal architecture distortion, intravascular fibrin clot, deposition of collagen fibers, vascular congestions and blood vessels containing thrombi, pneumocyte type II with inflammatory cell infiltration. The IHC staining for the innate immune cells such as antigen-presenting cells (APCs) including dendritic cells, Macrophages, and neutrophils showed a strong positive staining, while CD56 Natural killer (NK) cells showed negative staining. On the other hand, the specific immune cells including; CD20 B cells, CD3 T cells, and CD4 helper T cells, showed positive staining while CD8 Cytotoxic T cells showed negative staining. The lung autopsy samples from patients with COVID-19 confirmed the presence of APCs through the positive staining of CD21, CD1a, CD35, CD68, MPO, and CD15 expressed the virus recognition, proinflammatory cytokine production, and adaptive immune cells activation through CD3, CD4, and CD20 positive staining and the role of APCs in the severity of pulmonary infection and pathogenesis of SARS-CoV-2 infection however the absence of the CD56 NK and CD8 cytotoxic T explains the worse infection status for the patients.
Assuntos
Células Apresentadoras de Antígenos , Autopsia , COVID-19 , Pulmão , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/patologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/virologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , SARS-CoV-2/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Imuno-Histoquímica , Adulto , Antígenos CD/metabolismoRESUMO
BACKGROUND: The formation of stem cell clones enables close contact of stem cells inside. The gap junctions in such clone spheres establish a microenvironment that allows frequent intercellular communication to maintain self-renewal and functions of stem cells. Nevertheless, the essential gap junction protein for molecular signaling in clones is poorly known. METHODS: Primary human airway basal cells (hBCs) were isolated from brushing samples through bronchoscopy and then cultured. A tightly focused femtosecond laser was used to excite the local Ca2+ in an individual cell to initiate an internal Ca2+ wave in a clone to screen gap junction proteins. Immunoflourescence staining and clonogenicity assay were used to evaluate self-renewal and functions. RNA and protein levels were assessed by PCR and Western blot. Air-liquid interface assay was conducted to evaluate the differentiation potential. A Naphthalene injury mouse model was used to assess the regeneration potential. RESULTS: Herein, we identify Connexin 25 (Cx25) dominates intercellular Ca2+ communications in clones of hBCs in vitro to maintain the self-renewal and pluripotency of them. The self-renewal and in vitro differentiation functions and in vivo regeneration potential of hBCs in an airway damage model are both regulated by Cx25. The abnormal expression of Cx25 is validated in several diseases including IPF, Covid-19 and bronchiectasis. CONCLUSION: Cx25 is essential for hBC clones in maintaining self-renewal and functions of hBCs via gap junctions.
Assuntos
Conexinas , Regeneração , Humanos , Animais , Camundongos , Conexinas/metabolismo , Conexinas/genética , Diferenciação Celular , COVID-19/metabolismo , COVID-19/virologia , COVID-19/patologia , Junções Comunicantes/metabolismo , Autorrenovação Celular , Cálcio/metabolismo , Células Cultivadas , SARS-CoV-2/metabolismo , Masculino , Células-Tronco/metabolismo , Células-Tronco/citologiaRESUMO
The aim of this study was to determine the antiviral activity of cannabidiol (CBD) against SARS-CoV-2 infection. CBD is the second most studied cannabinoid obtained from Cannabis plants. We investigated the potential use of CBD, which has so far proven to have a positive effect on different diseases, in the SARS-CoV-2 infection. To test this, in vivo studies were carried out using K18-hACE2 transgenic mice. To reveal the potential therapeutic effect of the CBD at the histopathological and molecular level challenge experiments were performed. The study was designed with two groups (n = 10) and in the treatment group animals were infected with SARS-CoV-2 virus strain B.1.1.7 alpha before the administration of CBD. While the disease progressed and resulted in death in the control group that was infected by the virus alone, it was observed that the infection slowed down and the survival rate increased in the mice treated with CBD along with the virus. In this study, K18-hACE2 transgenic mice infected with the wild SARS-CoV-2 virus were used to investigate and prove the antiviral activity of CBD.
Assuntos
Enzima de Conversão de Angiotensina 2 , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Canabidiol , SARS-CoV-2 , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Canabidiol/farmacologia , Canabidiol/uso terapêutico , COVID-19/virologia , COVID-19/patologia , Modelos Animais de Doenças , Pulmão/virologia , Pulmão/patologia , Pulmão/efeitos dos fármacos , Camundongos Transgênicos , SARS-CoV-2/efeitos dos fármacos , Carga Viral/efeitos dos fármacosRESUMO
Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis.
Assuntos
COVID-19 , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina , Mesocricetus , Osteoartrite , Pirimidinas , SARS-CoV-2 , Animais , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Humanos , COVID-19/virologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/patologia , Osteoartrite/tratamento farmacológico , Osteoartrite/virologia , Osteoartrite/patologia , Osteoartrite/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Antagonistas dos Receptores de Endotelina/farmacologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Sulfonamidas/farmacologia , Cricetinae , Masculino , Tratamento Farmacológico da COVID-19 , Condrócitos/virologia , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/virologia , Cartilagem Articular/metabolismo , Cartilagem Articular/efeitos dos fármacos , Receptores de Endotelina/metabolismo , Endotelina-1/metabolismo , Feminino , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Histiocytoses are rare diseases characterised by infiltration of affected organs by myeloid cells with a monocyte or dendritic cell phenotype. Symptoms can range from self-resolving localised forms to multisystemic lesions requiring specific treatment. To demonstrate extremely rare cases of CD68-negative cardiac histiocytosis with expression of SARS-CoV-2 antigen in infiltrate cells. We demonstrated a case of Erdheim-Chester disease in a 67-year-old man with pericardial involvement and positive dynamics with vemurafenib treatment, an autopsy case of xanthogranulomatous myopericarditis in a 63-year-old man, surgical material of xanthogranulomatous constrictive pericarditis in a 57-year-old man, and an autopsy case of xanthogranulomatosis in a 1-month-old girl. In all cases, xanthogranuloma cells expressed CD163, many of them spike protein SARS-CoV-2, while CD68 expression was detected only in single cells. In this article, we demonstrated four cases of extremely rare CD68-negative cardiac xanthogranulomatosis in three adults and one child with expression of the spike protein SARS-CoV-2 in M2 macrophages. This potential indirect association between COVID-19 and the development of histiocytosis in these patients warrants further investigation. To substantiate this hypothesis, more extensive research is needed.
Assuntos
Antígenos CD , Antígenos de Diferenciação Mielomonocítica , COVID-19 , Histiocitose , SARS-CoV-2 , Humanos , COVID-19/metabolismo , COVID-19/patologia , COVID-19/complicações , COVID-19/virologia , Masculino , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos CD/metabolismo , Feminino , Pessoa de Meia-Idade , Idoso , SARS-CoV-2/metabolismo , Histiocitose/patologia , Histiocitose/metabolismo , Doença de Erdheim-Chester/metabolismo , Doença de Erdheim-Chester/patologia , Doença de Erdheim-Chester/diagnóstico , Glicoproteína da Espícula de Coronavírus/metabolismo , Lactente , Molécula CD68 , Receptores de Superfície CelularRESUMO
Introduction: In post-COVID survivors, transforming growth factor-beta-1 (TGF-ß1) might mediate fibroblast activation, resulting in persistent fibrosis. Methods: In this study, 82 survivors of COVID-19-associated ARDS were examined at 6- and 24-months post-ICU discharge. At 6-months, quantitative CT analysis of lung attenuation was performed and active TGF-ß1 was measured in blood and exhaled breath condensate (EBC). Results: At 6-months of ICU-discharge, patients with reduced DmCO/alveolar volume ratio exhibited higher plasma and EBC levels of active TGF-ß1. Plasma TGF-ß1 levels were elevated in dyspneic survivors and directly related to the high-attenuation lung volume. In vitro, plasma and EBC from survivors induced profibrotic changes in human primary fibroblasts in a TGF-ß receptor-dependent manner. Finally, at 6-months, plasma and EBC active TGF-ß1 levels discriminated patients who, 24-months post-ICU-discharge, developed gas exchange impairment. Discussion: TGF-ß1 pathway plays a pivotal role in the early-phase fibrotic abnormalities in COVID-19-induced ARDS survivors, with significant implications for long-term functional impairment.
Assuntos
COVID-19 , SARS-CoV-2 , Fator de Crescimento Transformador beta1 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , COVID-19/imunologia , COVID-19/complicações , COVID-19/patologia , Fibroblastos/metabolismo , Fibrose , Pulmão/patologia , Pulmão/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , Sobreviventes , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/sangueRESUMO
Chemokine receptors play diverse roles in the immune response against pathogens by recruiting innate and adaptive immune cells to sites of infection. However, their involvement could also be detrimental, causing tissue damage and exacerbating respiratory diseases by triggering histological alterations such as fibrosis and remodeling. This chapter reviews the role of chemokine receptors in the immune defense against SARS-CoV-2 infection. In COVID-19, CXCR3 is expressed mainly in T cells, and its upregulation is related to an increase in SARS-CoV-2-specific antibodies but also to COVID-19 severity. CCR5 is a key player in T-cell recruitment, and its suppression leads to reduced inflammation and viremia levels. Conversely, CXCR6 is implicated in the aberrant migration of memory T cells within airways. On the other hand, increased CCR4+ cells in the blood and decreased CCR4+ cells in lung cells are associated with severe COVID-19. Additionally, CCR2 is associated with an increase in macrophage recruitment to lung tissues. Elevated levels of CXCR1 and CXCR2, which are predominantly expressed in neutrophils, are associated with the severity of the disease, and finally, the expression of CX3CR1 in cytotoxic T lymphocytes affects the retention of these cells in lung tissues, thereby impacting the severity of COVID-19. Despite the efforts of many clinical trials to find effective therapies for COVID-19 using chemokine receptor inhibitors, no conclusive results have been found due to the small number of patients, redundancy, and co-expression of chemokine receptors by immune cells, which explains the difficulty in finding a single therapeutic target or effective treatment.
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COVID-19 , Receptores de Quimiocinas , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , SARS-CoV-2/imunologia , Receptores de Quimiocinas/metabolismoRESUMO
The 2019 outbreak of SARS-CoV-2 has caused a major worldwide health crisis with high rates of morbidity and death. Interestingly, it has also been linked to cancer, which begs the issue of whether it plays a role in carcinogenesis. Recent studies have revealed various mechanisms by which SARS-CoV-2 can influence oncogenic pathways, potentially promoting cancer development. The virus encodes several proteins that alter key signaling pathways associated with cancer hallmarks. Unlike classical oncogenic viruses, which transform cells through viral oncogenes or by activating host oncogenes, SARS-CoV-2 appears to promote tumorigenesis by inhibiting tumor suppressor genes and pathways while activating survival, proliferation, and inflammation-associated signaling cascades. Bioinformatic analyses and experimental studies have identified numerous interactions between SARS-CoV-2 proteins and cellular components involved in cancer-related processes. This review explores the intricate relationship between SARS-CoV-2 infection and cancer, focusing on the regulation of key hallmarks driving initiation, promotion and progression of cancer by viral proteins. By elucidating the underlying mechanisms driving cellular transformation, the potential of SARS-CoV-2 as an oncovirus is highlighted. Comprehending these interplays is essential to enhance our understanding of COVID-19 and cancer biology and further formulating strategies to alleviate SARS-CoV-2 influence on cancer consequences.
Assuntos
COVID-19 , Neoplasias , SARS-CoV-2 , Transdução de Sinais , Humanos , Neoplasias/virologia , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , COVID-19/virologia , COVID-19/patologia , SARS-CoV-2/fisiologia , Carcinogênese/genética , Animais , Proteínas Virais/metabolismo , Proteínas Virais/genéticaRESUMO
OBJECTIVE: Aim: To make a systematic review and meta-analysis of published data on the study of histological and immunohistochemical features of the placenta in women who had acute coronavirus infection associated with SARS-CoV-2 ("Covid" placentas) during pregnancy. PATIENTS AND METHODS: Materials and Methods: The search for literature data is based on the PRISMA methodology); the MEDLINE database (PubMed®) was searched using Medical Subject Headings terms from January 2020 to July 2023. The project was registered in the Open Sience Frame (Project Identifier: DOI 10.17605/OSF.IO/GDR3S, Registration DOI: https://doi.org/10.17605/OSF.IO/H2KPU). Preference was given to studies in which the description of placentas met the requirements of the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: Results: A total of 31 studies were included; the number of participants whose morphological and histological description of the placentas could be subjected to meta-analysis was 2401, respectively, in the group with a "Covid" history and 1910 - conditionally healthy pregnant women. Pathological changes in the placental complex were not detected in 42±19.62% of pregnant women with a history of Covid. Immunohistochemical examination of placentas preferably focuses on the detection of SARS-CoV-2 spike protein or ACE2. According to currently available studies, in the placentas of women who have had COVID-19 during pregnancy, there are no pathognomic histological patterns specific to this infection and direct damage to the placenta is rarely observed. Histological patterns in "covid" placentas are isolated, most often a combination of lesions in both the maternal and fetal malperfusion. CONCLUSION: Conclusions: According to currently available studies, in the placentas of women who have had COVID-19 during pregnancy, there are no pathognomic histological patterns specific to this infection and direct damage to the placenta is rarely observed. The probability of infection of the intrauterine fetus by the transplacental hematogenous route is the lowest compared to other routes, which, in our opinion, is a possible explanation for the high frequency of MVM without subsequent infection of the fetus.
Assuntos
COVID-19 , Placenta , Complicações Infecciosas na Gravidez , Feminino , Humanos , Gravidez , COVID-19/diagnóstico , COVID-19/patologia , Imuno-Histoquímica , Placenta/patologia , Placenta/virologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , SARS-CoV-2/isolamento & purificaçãoRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) has created a global pandemic with significant morbidity and mortality. SARS-CoV-2 primarily infects the lungs and is associated with various organ complications. Therapeutic approaches to combat COVID-19, including convalescent plasma and vaccination, have been developed. However, the high mutation rate of SARS-CoV-2 and its ability to inhibit host T-cell activity pose challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSCs-EVs) have shown promise in COVID-19 therapy because of their immunomodulatory and regenerative properties. MicroRNAs (miRNAs) play crucial regulatory roles in various biological processes and can be manipulated for therapeutic purposes. OBJECTIVE: We aimed to investigate the role of lyophilized MSC-EVs and their microRNAs in targeting the receptors involved in SARS-CoV-2 entry into host cells as a strategy to limit infection. In silico microRNA prediction, structural predictions of the microRNA-mRNA duplex, and molecular docking with the Argonaut protein were performed. METHODS: Male Syrian hamsters infected with SARS-CoV-2 were treated with human Wharton's jelly-derived Mesenchymal Stem cell-derived lyophilized exosomes (Bioluga Company)via intraperitoneal injection, and viral shedding was assessed. The potential therapeutic effects of MSCs-EVs were measured via histopathology of lung tissues and PCR for microRNAs. RESULTS: The results revealed strong binding potential between miRNAâmRNA duplexes and the AGO protein via molecular docking. MSCs-EVs reduced inflammation markers and normalized blood indices via the suppression of viral entry by regulating ACE2 and TMPRSS2 expression. MSCs-EVs alleviated histopathological aberrations. They improved lung histology and reduced collagen fiber deposition in infected lungs. CONCLUSION: We demonstrated that MSCs-EVs are a potential therapeutic option for treating COVID-19 by preventing viral entry into host cells.
Assuntos
COVID-19 , Vesículas Extracelulares , Células-Tronco Mesenquimais , MicroRNAs , SARS-CoV-2 , COVID-19/terapia , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Animais , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Células-Tronco Mesenquimais/metabolismo , Humanos , Masculino , Mesocricetus , Internalização do Vírus , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Simulação de Acoplamento Molecular , Simulação por Computador , Cricetinae , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
Avascular necrosis (AVN) is a debilitating condition characterized by bone tissue death due to inadequate blood supply, leading to joint dysfunction and collapse. This study investigates the potential association between AVN and COVID-19, focusing on genetic factors such as NOS3 polymorphisms. A total of 180 individuals were included, comprising 120 COVID-19 patients and 60 healthy controls. Clinical, haematological, biochemical, and genetic parameters were assessed. Results revealed significant differences in respiratory and heart rates, haematological counts, and biochemical markers between AVN and control groups. Genetic analysis showed a higher prevalence of the TG genotype and G allele in NOS3 rs1799983 polymorphism among AVN patients. Additionally, NOS3 rs2070744 polymorphism correlated with various clinical parameters, including blood pressure, heart rate, and haematological indices. This study highlights the potential role of genetic factors in predisposing individuals to AVN following COVID-19 infection.
Assuntos
COVID-19 , Óxido Nítrico Sintase Tipo III , Osteonecrose , Feminino , Humanos , Masculino , Estudos de Casos e Controles , COVID-19/genética , COVID-19/complicações , COVID-19/patologia , Predisposição Genética para Doença , Genótipo , Óxido Nítrico Sintase Tipo III/genética , Osteonecrose/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit ß, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.
Assuntos
COVID-19 , Sequenciamento do Exoma , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , COVID-19/genética , COVID-19/virologia , COVID-19/patologia , Bulgária , Feminino , Masculino , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Pessoa de Meia-Idade , Idoso , Adulto , Mutação , Cílios/patologia , Cílios/genéticaRESUMO
The COVID-19, caused by SARS-CoV-2, first affects the respiratory tract but evidence is emerging that the virus, reaching the central nervous system (CNS), can lead to severe neurological disorders. In particular, CoV infection could cause an acceleration of the neurodegenerative process. On the other hand, patients diagnosed with Alzheimer's disease (AD) develop more serious forms of COVID-19 with worse relapses. Therefore, understanding the connection between the two pathologies, AD and infection by coronavirus, could help in the development of new therapeutic approaches to counter them. We used the SH-SY5Y cell line differentiated into neurons, as widely used in studies of AD if supplemented with exogenous fibrillary ß-amyloid (Aß). As a glial counterpart, human microglia (HMC3) and astrocytic (D54MG) cell lines were used to create co-cultures with neurons via transwell systems. In these experimental models, we generated infection with the Human Coronavirus OC43 (HCoV-OC43), a low-risk model of SARS-CoV-2. Our results suggest that the infection by HCoV-OC43 leads to a neurotoxic effect not depending on an already present event of Aß deposition. Indeed, unlike microglia, neurons and even more astrocytes are susceptible to CoV infection and, although the infection does not show a cytotoxic effect in the neurons in the first few days, significant alterations at a biochemical and morphological level have been observed, suggesting that the neurons are reacting to a stressful condition, including the prodromal and neurodegenerative features of AD. Interestingly, the interaction of infected astrocytes with the neurons resulted in the manifestation of signs of neurodegeneration, such as amyloid-beta deposition. By using exogenous fibrillary Aß, as an AD in vitro model, our data suggest that there is an aggravating effect both on the infection itself and on the neurological disease progression. In conclusion, the results of this study suggest a causal interplay between HCoV-OC43 and neurological diseases and demonstrate that the co-presence of different CNS cell populations is the necessary condition to study the pathogenic effects in vitro as a whole.