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Introduction: SARS-CoV-2 is responsible for the current global pandemic. SARS-CoV-2 infection underlies the novel viral condition coronavirus disease 2019 (COVID-19). COVID-19 causes significant pulmonary sequelae contributing to serious morbidities. The pathogenesis of COVID-19 is complex with a multitude of factors leading to varying levels of injury numerous extrapulmonary organs. This review of 124 published articles documenting COVID- 19 autopsies included 1,142 patients. Method(s): A PubMed search was conducted for COVID-19 autopsy reports published before March 2021 utilizing the query COVID-19 Autopsy. There was no restriction regarding age, sex, or ethnicity of the patients. Duplicate cases were excluded. Findings were listed by organ system from articles that met selection criteria. Result(s): Pulmonary pathology (72% of articles;866/1142 patients): diffuse alveolar damage (563/866), alveolar edema (251/866), hyaline membrane formation (234/866), type II pneumocyte hyperplasia (165/866), alveolar hemorrhage (164/866), and lymphocytic infiltrate (87/866). Vascular pathology (41% of articles;771/1142 patients): vascular thrombi (439/771)-microvascular predominance (294/439)-and inflammatory cell infiltrates (116/771). Cardiac pathology (41% of articles;502/1142 patients): cardiac inflammation (186/502), fibrosis (131/502), cardiomegaly (100/502), hypertrophy (100/502), and dilation (35/502). Hepatic pathology (33% of articles;407/1142 patients): steatosis (106/402) and congestion (102/402). Renal pathology (30% of articles;427/1142 patients): renal arteries arteriosclerosis (111/427), sepsis-associated acute kidney injury (81/427) and acute tubular necrosis (77/427). Conclusion(s): This review revealed anticipated pulmonary pathology, along with significant extrapulmonary involvement secondary to COVID-19, indicating widespread viral tropism throughout the human body. These diverse effects require additional comprehensive longitudinal studies to characterize short-term and long-term COVID-19 sequelae and inform COVID-19 treatment.
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The development of coronavirus infection outbreak into a pandemic, coupled with the lack of effective COVID-19 therapies, is a challenge for the entire pharmaceutical industry. This study aimed to assess the treatment and preventive efficacy of the amino acid-peptide complex (APC) in male Syrian hamsters infected with SARSCoV-2 (intranasal administration of 26 mul of the virus culture, titer of 4 x 104 TCD50/ml). In a modeled COVID-19 case, APC administered for treatment and preventive purposes reduced lung damage. Compared to the positive control group, test group had the lung weight factor 15.2% smaller (trend), which indicates a less pronounced edema. Microscopic examination revealed no alveolar edema, atypical hypertrophied forms of type II alveolocytes, pulmonary parenchyma fibrinization. The macrophage reaction intensified, which is probably a result of the APC-induced activation of regenerative processes in the lung tissues. Spleens of the animals that received APC for therapeutic and preventive purposes were less engorged and had fewer hemorrhages. The decrease of body weight of the test animals that received APC for treatment and prevention was insignificant (p < 0.05), which indicates a less severe course of COVID-19. Administered following a purely therapeutic protocol, APC proved ineffective against SARS-CoV-2 post-infection. Thus, APC-based drug used as a therapeutic and preventive agent reduces pulmonary edema and makes morphological signs of lung tissue damage less pronounced in male Syrian hamsters infected with SARS-CoV-2.Copyright © Extreme Medicine.All right reserved.
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The series of autopsies reported since the beginning of the pandemic have highlighted several patterns of lung damage, both isolated and combined. The factors influencing the occurrence of these different tissue responses to viral aggression by SARS-CoV-2 have not yet been determined. In asymptomatic patients or patients with respiratory symptoms who were not ventilated, lymphocyte pneumonia associated with type II pneumocyte atypical hyperplasia and a few hyaline membranes or focal lesions of acute fibrinous pneumonia have been observed. In critically ill patients, the most frequent pattern is diffuse alveolar damage with interstitial lymphoid infiltration, type II pneumocyte atypia and, very often, capillary or arteriolar microthromboses and/or endothelitis. The precise description of these lesions, which is becoming more and more consensual, makes it possible to understand the favourable effects of corticosteroid therapy in seriously ill patients and the evolution under ventilation towards fibrosis.Copyright © ERS 2021.
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Study objective. It has been shown that human common viruses are new target genes for host cell dioxin receptor transcriptional (AhR-ARNT) complex initially proven to up-regulate mammalian genes containing dioxin-response elements (DRE) in the promoters [doi:10.1016/j.ijid.2012.05.265]. Initially, transactivation of HIV-1 and HBV by 2,3,7,8-tetrachlodibenzop- dioxin (TCDD) at low nanomolar range was demonstrated [doi:10.3109/00498259309057034]. Noteworthy, transactivation of human cytomegalovirus (CMV) was shown with 0.3 ppt dioxin, i.e. lower than its current background level in the general population (~3.0 ppt). Recently, reactivation of CMV infection was found to influence worse clinical outcome following SARS-CoV-2 infection (doi: 10.1186/s12979-020- 00185-x). Other findings showed that CMV and herpes simplex virus 1 (HSV-1) reactivation were observed in immunocompetent patients with COVID-19 acute respiratory distress syndrome (ARDS) (doi.org/10.1186/s13054-020-03252-3). Addressing occurrence of Herpesviridae reactivation in severe COVID-19 patients, and still unspecified real triggers of CMV and HSV-1 reactivations, we tested TCDD, which current body burden (DBB) ranges from 20 pg/g (TEQ in fat) in general population to 100 pg/g in older people. Methods. In Silico quantitation of active DRE in promoters of viral genes. Virus DNA hybridization assay. Clinical and epidemiological analyses. Results and Discussion. In this study, a computational search for DRE in CMV and HSV-1 genes was performed by SITECON, a tool recognizing potentially active transcriptional factor binding sites. In silico analysis revealed in regulatory region of CMV IE genes from 5 to 10 DRE, and from 6 to 8 DRE in regulatory region of HSV-1 IE genes.We established that a low picomolar TCDD can trigger up-regulation of CMV and HSV-1 genes via AhR:Arnt transcription factor in macrophage(doi.org/10.1016/ j.ijid.2012.05.265) and glial human cell lines (doi.org/10.1016/j. jalz.2016.06.1268), respectively. In fact, viral reactivation may be triggered in COVID-19 ARDS patients by higher pulmonary TCDD concentrations, because "lipid storm" within lungs of severe COVID-19 patients has been recently reported (doi.org/ 10.1101/2020.12.04.20242115). TCDD is known as the most potent xenobiotic, which bioaccumulates and has estimation half-life in humans of up to 10 yr. Due to hydrophobic character (Log P octanol/water: 7.05), TCDD partitions into inflammatory lipids in lung tissue thus augmenting its local concentration. Population-based epidemiological data on SARS-CoV-2 first wave of pandemic revealed high level of CMV seropositivity and cumulative mortality rate 4.5 times in Lombardi region of Italy, where after Seveso industrial accident TCDD plasma level in pre-exposed subjects is 15 times the level in rest of Italy (doi. org/10.3389/fpubh.2020.620416). Also, Arctic Native (AN) peoples consume dioxin-contaminated fat in seafood and have TCDD DBB, i.e. 7 times that in general population. To the point of this paper, their COVID-19 mortality is 2.2 times of that among non-AN Alaskans (doi: 10.15585/mmwr.mm6949a3). Conclusion(s): TCDD in the picomolar range may trigger CMV expression in lung cells and commit virus to the lytic cycle, which can be applied to reactivation of Herpesviridae infection in immunocompetent patients with COVID-19 ARDS syndrome.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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Background: The continuous evolution of SARS-CoV-2 in the diverse immune landscape (natural, vaccine, hybrid) is giving rise to novel immune escape mutations. So far, the resulting new variants (BA.1, BA.2, BA.2.12.1) were observed to cause mild infections, however, BA.5 infections are associated with an increased risk of hospitalization.1 Therefore it is essential to investigate the pathogenesis of BA.5. Method(s): Here we compared the pathogenicity of Pre-Omicron (B.1.351) and Omicron (BA.1, BA.2.12.1, and BA.5) variants in wild-type C57BL/6J mice and K18-hACE2 mice. The virus replication kinetics was also studied in human Calu3, pulmonary alveolar type 2 (AT2) cells, and airway organoids (HAO). Cell-to-cell spread of virus was measured by syncytia formation assay and immunohistochemistry (IHC) of infected lungs. Result(s): In the results, infection in C57BL/6J mice showed severe weight loss ( >15%) for B.1.351 infected mice and moderate ( >5%) for BA.5 infected. C57BL/6J mice showed higher virus replication of B.1.351 followed by BA.5, BA.1, and BA.2.12.1. At the peak of virus replication (2 days) plaque-forming units from lung extract of BA.5 infected mice were two, and three logs higher compared to BA.1 and BA.2.12.1 respectively. BA.5 infection was lethal to 80% of infected K18-hACE2 mice, whereas the mice looked normal after infection with BA.1 and BA.2.12.1. BA.5 infected mice showed high virus replication in brain tissue. Surprisingly the syncytia formation assay and IHC for BA.5 was comparable to that of B.1.351, indicating the higher cell-to-cell spread of BA.5 and B.1.351 compared to BA.1 and BA.2.12.1, which is one of the measures of pathogenicity. Calu3 and HAO showed the same trend of virus replication as was observed in-vivo experiments however AT2 cells were found to be resistant to BA.5 replication. Conclusion(s): These results suggest that the BA.5 variant (lineage) of Omicron has the potential to regain the pathogenicity as it shows increased virulence compared to other Omicron sub-variants. Lethal infection of BA.5 in K18-hACE2 mice may be attributed to catastrophic encephalitis and increased cell-to-cell spread.
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Background and objectives: SARS-C0V-2 infections have varied manifestations among individuals ranging from asymptomatic or mild symptoms to severe disease and death. This study is done to look into various histopathological changes in lung, liver, and kidney tissues among Covid19 positive autopsies with cellular tropism and viral load among various organs by immunohistochemistry (IHC) for the SARS-C0V-2 viral marker. Method(s): A prospective descriptive study of core biopsies from covid19 positive autopsies from the lung, liver, and kidneys were taken from 20 cases. A routine histopathological examination of the tissues with IHC staining for SARS-CoV-2 cocktail antibodies was performed and assessed. Result(s): Histopathological changes in the lung, liver, and kidney tissues showed changes of varying severity. On IHC, in the lung, the tropism for SARS-CoV-2 was seen in pneumocytes, bronchial epithelial cells, endothelial cells, and macrophages. In the kidney, tropism was seen towards tubular epithelial cells and endothelial cells. In the liver, hepatocytes and bile duct epithelial cells were positive. Variable viral density was seen in different organs which varied from case to case. The density of the viral load was highest in the lung and lower in the kidney and least in the liver. Conclusion(s): In this study the various histopathological changes and cellular tropism of the SARS-CoV-2 among Lung, liver, and kidney tissues have been described and compared with various similar studies across the globe.Copyright © 2023 International Journal of Life Sciences Biotechnology and Pharma Research. All rights reserved.
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Purpose of Study: COVID pneumonia caused by SARS-CoV-2 can result in a depletion of surfactant & lung injury, which resembles neonatal respiratory distress syndrome. Exogenous surfactant has shown promise as a therapeutic option in intubated hospitalized patients. Our preliminary data in human lung organoids (LOs) with a deficiency of surfactant protein B (SP-B) showed an increased viral load compared to normal LOs. Single cell RNA sequencing (scRNAseq) revealed that SP-B-deficient cells showed increased viral entry genes (ACE2 receptor) & dysregulated inflammatory markers emanating from the lung cells themselves. Our objective was to determine: (1) cell-specific transcriptional differences between normal & SP-B deficient human lung cells after infection with SARS-CoV-2 and (2) a therapeutic role of SP-B protein & surfactant in COVID-19 pneumonia. Methods Used: We used normal and SP-B mutant (homozygous, frameshift, loss of function mutation p.Pro133GlnfsTer95, previously known as 121ins2) human induced pluripotent stem cells (hiPSC) and differentiated them into 3D proximal lung organoids. The organoids were infected with the delta variant of SARS-CoV-2 for 24 hours at an MOI of 1. Infected and uninfected organoids were fixed in trizol in triplicate and underwent processing for bulk RNA sequencing. We tested for differentially expressed genes using the program DEseq. We also plated normal iPSC derived lung organoids as a monolayer and pre-treated them with 1mg/ml of Poractant alfa or 5 uM of recombinant SP-B protein. The delta strain of SARS-CoV-2 was added to the 96 wells at an MOI of 0.1 for one hour with shaking, then an overlay with DMEM/CMC/FBS was added and left on for 23 hours. The plate was fixed and stained for nucleocapsid (NC) protein. Summary of Results: Bioinformatic analysis of the bulk RNA sequencing data showed an increase in the multiple cytokines and chemokines in the SP-B mutant LOs compared to control. We also saw differential gene expression patterns in the SP-B mutant LOs including a reduction in SFTPC, FOXA2, and NKX2-1 and an increase in IL1A, VEGFA, PPARG and SMAD3. In the exogenous surfactant experiments, there was a decrease in total expression of viral NC in the Poractant alfa & rSP-B-treated cells compared to SARS-CoV-2 infection alone (p<0.001). Conclusion(s): Surfactant modulates the viral load of SARS-CoV-2 infection in the human lung. Deficiency in SP-B results in the dysregulation of the lung epithelial inflammatory signaling pathways resulting in worsening infections.
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Background: Plasmacytoid dendritic cells (pDCs) are the major producer of type I IFNs (IFN-I), the critically important antiviral cytokines against SARS-CoV- 2. Although pDCs can sense cell-free SARS-CoV-2 virions, it is unknown whether they can detect infected cells to produce IFN-I. Since cell-to-cell transmission accounts for 90% of SARS-CoV-2 infections (Zeng et al., 2022), we examined the relevance of pDC sensing of infected cells in SARS-CoV-2 infection and whether the virus exploits this pathway to evade IFN-I responses. Method(s): LSPQ1, the first SARS-CoV-2 clinical isolate received from the Public Health Laboratory of Quebec, was used as a prototype virus. SARS-CoV-2 variants of concerns (VOCs) were also used. PBMCs or enriched pDCs were cocultured with mock-infected or SARS-CoV-2-infected HeLa-hACE2 or Calu-3. Either PBMCs, enriched pDCs, or HeLa-hACE2 were pretreated with anti-human ICAM-1 antibody or isotype control. The conjugate formation was determined by flow cytometry. Polarized Caco cells were used to validate critical data. Result(s): Upon sensing infected cells, PBMCs release 6-fold more IFN-I than they do when exposed to cell-free virions. Antibody-mediated depletion of pDCs from PBMCs abolishes IFN-I secretion. Direct contact of pDCs with infected cells is required for sensing since the use of a transwell membrane reduces IFN-I release by 85%. Infected cells form conjugates with pDCs more frequently (3.2-fold higher) than uninfected cells. Blocking ICAM-1 on infected cells or pDCs impacts conjugate formation and significantly suppresses IFN-I production by 55-80%, suggesting bidirectional interaction. Moreover, human lung cells infected with VOCs are sensed to a different extent with the alpha variant being the least efficiently sensed by pDCs compared to the delta or omicron strains. Even though SARS-CoV-2 is primarily released from the apical domain of polarized infected Caco cells, sensing of infected cells does occur upon direct contact of pDCs with the basolateral domain, highlighting how pDCs antiviral responses might be triggered in respiratory tissues. Conclusion(s): pDC sensing of infected cells accounts for the vast majority of IFN-I released during SARS-CoV-2 infection. ICAM-1 promotes physical contact between pDCs and infected cells, thus leading to efficient sensing. Differential pDC sensing of SARS-CoV-2 VOC-infected cells suggests that some VOCs might manipulate the interactions of pDCs with infected cells to limit IFN-I responses.
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Background: Natural killer (NK) cells play a critical role in control of viral infections. However, empirical evidence thus far has been unclear on the role of NK cells in pathogenesis and control of SARS-CoV-2 infection with some research suggesting NK cell accumulation as beneficial while others indicate it as deleterious. To address this crucial deficit in understanding, we employed a non-human primate infection model with a validated experimental NK cell depletion technique. Method(s): A total of 12 experimentally naive (75% female) cynomolgus macaques (CM) of Cambodian origin were used in this study. Six CM were NK cell-depleted using an anti-IL-15 neutralizing antibody, while six controls received placebo, prior to intranasal and intratracheal challenge with the SARS-CoV-2 Delta variant at a TCID50 of 1X105. The cohort was monitored for five weeks with scheduled blood, colorectal (CR) biopsies, and lymph node (LN) collections. Total envelope and sub-genomic viral loads (VL) were measured in the nasal cavity, throat, and bronchoalveolar lavage (BAL). 23-color flow cytometry, pathology, and 27-plex inflammatory analyte Luminex analyses were conducted. Statistical tests used were Mann-Whitney U and Spearman's Correlation. Result(s): Control CM exhibited an increase in the frequency of circulating NK cells, reaching a peak at 10 days post-infection (DPI) and returning to baseline by 22DPI. Simultaneously, NK cells expressing activation and tissue retention marker, CD69, also significantly increased. Cytotoxic NK cells were positively associated with VL (r=0.66;p=0.02), suggestive of a virus-induced mobilization. Total experimental NK cell ablation was verified in blood, CR, and LN of NK celldepleted CM, which had higher VL compared to controls in all tissues evaluated, reaching significance at 10DPI (p=0.01) and demonstrated a longer duration of viremia. Although Luminex measures were similar in plasma, BAL samples from NK cell-depleted CM had universally higher concentrations of inflammatory mediators, most notably a 25-fold higher concentration of IFN-alpha compared to controls. Lung pathology scores were also higher in NK cell-depleted CM with increased evidence of fibrosis, syncytia, pneumocyte hyperplasia, and endothelialitis. Conclusion(s): Overall, we find significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data suggest adjunct therapies for infection could largely benefit from NK cell-targeted approaches.
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Since December 2019, an outbreak of a novel coronavirus (SARS-CoV-2) infection causing COVID-19 disease has influenced the whole world. Angiotensin converting enzyme 2 (ACE2) receptors on type 2 pneumocytes in humans were determined as the entry for SARSCoV-2. Receptor binding and subsequently endocytosis of ACE2 diminish the cell membrane expression and also the function of ACE2. ACE2 is an enzyme involved in bradykinin metabolism. Lys-des-Arg9-BK occured with enzymatic cleaving of Lys-BK derived from low molecular weight kininogen is inactivated by ACE2 in tissues and it is a vasodilator agent having its own receptor named bradykinin B1. Non-metabolized Lys-des-Arg9-BK can be the reason for tissue vasodilation and increased vascular permeability in the patients with COVID-19. Increased bradykinin levels in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) do not cause increased SARS-CoV-2 infection or more severe disease. Although SARS-CoV-2 infection does not result in increased bradykinin levels, it can increase Lys-des-Arg9-BK levels.Copyright © 2020 Bilimsel Tip Yayinevi. All rights reserved.
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Introduction/Aim: Coronavirus disease 2019 (COVID-19) is a novel viral infection that can cause severe pneumonia and acute respiratory failure;however, the mechanism of disease progression is still unclear. The aim of this study is to evaluate inflammatory cells in the lung by analysing cell populations of bronchial aspirates of COVID-19 pneumonia. Method(s): Eligible cases were diagnosed as COVID-19, confirmed by SARS-CoV-2 PCR. All cases had developed severe COVID-19 pneumonia and undergone invasive positive pressure ventilation for the treatment of respiratory failure. Bronchial aspirates were collected during endotracheal intubation, and SARS-CoV-2 PCR was done. The populations of obtained cells from bronchial aspirates were examined by Giemsa staining and immunohistochemical staining of CD3, CD4, CD8, CD20 and CD68 antigens. Bronchial aspirates were cultured to confirm respiratory bacterial co-infections. Result(s): A total of 14 cases (median age 70;eleven male and three female) were enrolled in this study. Their bronchial aspirates were all positive for SARS-CoV-2 PCR. Bacterial co-infections were developed in 10 cases, including 6 cases of pneumonia/respiratory tract infection, 2 cases of sepsis, and 2 cases of urinary tract infection. Cell populations of bronchial aspirates with or without bacterial co-infections were as follows: neutrophils 33.0% vs. 21.5%;CD3+ mononuclear cells (MNCs) 2.5% vs. 5.8%;CD4+ MNCs 4.6% vs. 3.4%;CD8+ MNCs 3.5% vs. 5.2%;CD20+ MNCs 0.2% vs. 0.1%;CD68+ MNCs 39.7% vs. 38.8%, respectively. Conclusion(s): CD68 antigen is mainly expressed in monocytes/macrophages. CD68+ MNCs were dominant in bronchial aspirates of the cases with severe COVID-19 pneumonia. Our data suggests that CD68+ MNCs, presumably macrophages, would play an essential role during the innate immune response to acute SARS-CoV-2 infection in the lung.
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The approval of mRNA vaccine technique against COVID-19 opens a door to research and the creation of new drugs against different infectious pathologies or even cancer, since for several diseases the therapeutic options are limited, and different viral diseases are treated only symptomatically. For these reasons, this study proposed a hypothesis supported by biological studies, that it provides a theoretical basis for the possible development of a drug that used the mRNA technique and the ribonucleolytic action of a ribonuclease for a possible antiviral therapy, and analyzed a future perspective of this technique in order to provide a bibliographic basis on this hypothesis and motivate researchers to carry out biological studies on this topic.Copyright © 2022, Health Biotechnology and Biopharma. All rights reserved.
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Coronaviruses are a leading cause of emerging life-threatening diseases, as evidenced by the ongoing coronavirus disease pandemic (COVID-19). According to complete genome sequence analysis reports, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, has a sequence identity highly similar to the earlier severe acute respiratory syndrome coronavirus (SARS-CoV). The SARS-CoV-2 has the same mode of transmission, replication, and pathogenicity as SARS-CoV. The SARS-CoV-2 spike protein's receptor-binding domain (RBD) binds to host angiotensin-converting enzyme-2 (ACE2). The ACE2 is overexpressed in various cells, most prominently epithelial cells of the lung (surface of type 1 and 2 pneumocytes), intestine, liver, kidney, and nervous system. As a result, these organs are more vulnerable to SARS-CoV-2 infection. Furthermore, renin-angiotensin system (RAS) blockers, which are used to treat cardiovascular diseases, intensify ACE2 expression, leading to an increase in the risk of COVID-19. ACE2 hydrolyzes angioten-sin-II (carboxypeptidase) to heptapeptide angiotensin (1-7) and releases a C-terminal amino acid. By blocking the interaction of spike protein with ACE2, the SARS-CoV-2 entry into the host cell and inter-nalization can be avoided. The pathogenicity of SARS-CoV-2 could be reduced by preventing the RBD from attaching to ACE2-expressing cells. Therefore, inhibition or down-regulation of ACE2 in host cells represents a therapeutic strategy to fight against COVID-19. However, ACE2 plays an essential role in the physiological pathway, protecting against hypertension, heart failure, myocardial infarction, acute respiratory lung disease, and diabetes. Given the importance of ACE's homeostatic role, targeting of ACE2 should be realized with caution. Above all, focusing on the SARS-CoV-2 spike protein and the ACE2 gene in the host cell is an excellent way to avoid viral mutation and resistance. The current review summarises the sequence analysis, structure of coronavirus, ACE2, spike protein-ACE2 complex, essential structural characteristics of the spike protein RBD, and ACE2 targeted approaches for anti-coronaviral drug design and development.Copyright © 2022 Bentham Science Publishers.
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Introduction: The molecular mechanisms linked to the pathology of severe COVID-19 and its outcomes are poorly described. Aim(s): To analyze the proteomic profile of bronchial aspirates (BAS) samples from critically ill COVID-19 patients in order to identify factors associated with the disease and its prognosis. Method(s): Multicenter study including 74 critically ill non-COVID-19 and COVID-19 patients. BAS was obtained by bronchoaspiration after invasive mechanical ventilation (IMV) initiation. Proximity extension assay (PEA) technology was used for proteomic profiling. Random forest (RF) statistical models were used to predict the variable importance. Result(s): After adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-alpha showed differences between COVID-19 and non-COVID-19 patients. Reduced levels of ENTPD2 and PTN were observed in non-survivors, even after adjustment. AGR2, NQO2, IL-1alpha, OSM and TRAIL, were the top five strongest predictors for ICU mortality and were used to build a prediction model. PTN (HR=4.00) ENTPD2 (HR=2.14) and the prediction model (HR=6.25) were associated with higher risk of death. In survivors, FCRL1, NTF4 and THOP1 correlated with lung function (DLCO levels) 3-months after hospital discharge. Similar findings were observed for Flt3L and THOP1 and radiological features (TSS). The proteins identified are expressed in immune and non-immune lung cells. A poor control of viral infectivity and an inappropriate reparative response seems to be linked to the disease and fatal outcomes, respectively. Conclusion(s): In critically ill COVID-19 patients, specific proteomic profiles are associated with the pathology, mortality and lung sequelae.
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Patients with severe COVID-19-associated pneumonia are at risk to develop pulmonary fibrosis. To study the underlying mechanisms, we aim to develop advanced cell culture models that reliably reflect COVID-19-related profibrotic microenvironment. To identify key cellular players, we performed pilot immunohistochemistry analysis on lung tissue from COVID-19 patients with fibrosis collected during autopsy. Results revealed diffuse alveolar damage with macrophage infiltration, and myofibroblast accumulation with enriched collagen deposition surrounding the damaged alveoli. To mimic SARS-CoV-2 infection in alveoli, we infected human primary type II alveolar epithelial cells (AEC2) and found enhanced signaling of profibrotic cytokine transforming growth factor beta (TGFbeta) in some donors. To recreate the early fibrotic niche, an alveolar-macrophage-fibroblast (AMF) tri-culture model was established. After infecting AEC2 with SARS-CoV-2 in this AMF model, gene expression analysis provided evidence for fibroblast-to-myofibroblast transition. Furthermore, we found that overexpression of SARS-CoV-2 papain-like protease (PLpro) can promote TGFbeta signaling in HEK293T and A549 cells. After infecting AEC2 with SARS-CoV-2 PLpro lentivirus in the AMF model, we found signs of epithelial-to-mesenchymal transition and fibroblast-to myofibroblast transition. In future studies, we will use a detailed analysis of COVID-19-associated lung fibrosis with other types of lung fibrosis, to further refine COVID-19-related fibrosis models, including lung-on-chip models.
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Background: COVID 19 has two-way interaction with Type II Diabetes Mellitus. First, patient with DM are more prone for developing severe COVID 19. Second, moderate to severe COVID 19 can present with new onset DM or may lead to hyperglycaemia and hyperglycaemic complications in Type II DM patients. In this report we present 4 cases of COVID 19 associated Hyperglycaemic Complication (3 with Diabetic Ketoacidosis and 1 with Hyperglycaemic hyperosmolar state). Method(s): Case Series of patients admitted to Thumbay Hospital, Ajman. Result(s): We report 4 cases of COVID 19 patients who presented to us with hyperglycaemic complications. There of them had features of Diabetic Ketoacidosis and one had Hyperglycaemic hyperosmolar state. All were treated with IV Insulin infusion and IV Fluids. COVID 19 infection was managed as per MOH protocol. All patients recovered well and were discharged in stable condition. Discussion(s): COVID 19 is associated with new onset DM or may lead to hyperglycaemic complications in patients with Type II DM. There are three pathophysiological processes which may be responsible for this finding. One, SARS-CoV-2 virus is known to enter the body through angiotensin-converting enzyme (ACE) II receptors in the pulmonary pneumocytes leading to infection and inflammation. Similar ACE-II receptors are also expressed in key metabolic organs and tissues, including pancreatic beta cells, adipose tissue, the small intestine, and the kidneys. Direct infection of pancreatic beta-cells with SARS-CoV-2 virus with beta-cell cell injury is likely the underlying mechanism for development of new onset diabetes and hyperglycaemia in existing diabetic patients. Such direct beta cell infection can cause hyperglycaemic complications in asymptomatic or mild COVID 19 as well. Two, moderate to severe COVID 19 is associated with hyperinflammatory immune response leading to marked rise in inflammatory mediators such as C-reactive protein and ferritin. Such hyperinflammatory response can also lead to hyperglyacemia in patients with diabetes mellitus. Three, corticosteroids are mainstay treatment of patients with moderate to severe COVID 19 and would definitely contribute to worsening of hyperglycaemia in these patients. Our patients presented to us with hyperglycaemic complications before initiation of any treatment. It is likely that such a situation would be due to direct infection and destruction of beta cells with SARS-CoV-2 virus infection. Conclusion(s): Type II Diabetes Mellitus patients are high risk of developing hyperglycaemic complications due to COVID 19. This can lead to increased morbidity and mortality. Patients with Type II DM should seek medical attention even if they have mild to asymptomatic COVID 19 to monitor for hyperglycaemic complication which can develop irrespective of severity of stage of illness.
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Originally thought to be a respiratory pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has been shown to cause a dizzying array of symptoms, including all major organ systems of the human body. As time elapsed, new strains of the virus have emerged, validating concerns about genetic mutation. No single treatment has proven beneficial in treating the consequences, and the world has been left at the mercy of this deadly pathogen. It has been proven that COVID-19 can cause strokes, myocardial infarcts, mesenteric infarcts, acute limb ischemia, and a wide array of other symptomatology. This review aimed to evaluate whether there exists an association between COVID-19 and pancreatitis. Forty publications (34 case reports and 4 case series) were included in the review. In total, 44 cases of acute pancreatitis (38 cases of acute edematous pancreatitis and 6 cases of necrotizing pancreatitis) in COVID-19 patients without any predisposing factors have been published since January 2020. Fortunately, only 4 (9.1%) of these patients were reported to have died. Although the exact mechanism by which COVID-19 causes pancreatitis is still unclear, studies so far have reported it as a multifactorial phenomenon. COVID-19 associated pancreatic injury is thought to involve direct cellular damage via local replication of SARS-CoV-2 within pancreatic cells, as they express angiotensin-converting enzyme 2 receptors even more strongly than lung cells. Our review concludes that acute pancreatitis should be kept in the differential list of all COVID-19 patients with gastrointestinal manifestations, especially in patients with acute abdomen.Copyright © 2023, Society of Gastrointestinal Intervention.
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Aim: COVID-19 infection has affected the whole world. It has been speculated that the virus might hold on to angiotensin-converting enzyme 2 (ACE 2) surfaces of type 2 alveolar cells. ACE inhibitors and angiotensin receptor antagonists (ARBs) are essential antihypertensive and cardiac failure drugs in the guidelines. In this study, we aimed to find the effect of these drugs on clinical, laboratory courses, and outcomes of COVID-19 patients. Material(s) and Method(s): We included 109 patients in this study. There were 43 patients in the ACE/ARB group and 66 patients in the non-ACE/ARB group. The mean age was 60 years in the ACE/ARB group and 52 years old in the non-ACE/ARB group. Basal symptoms, hemogram, CRP, D-dimer, LDH, Ferritin, AST, duration of hospitalization, percentage of intensive care unit (ICU) need, length of stay in ICU were compared between the groups. Result(s): The mean age in the ACE/ARB group was higher than in the other group and was statistically significant (p=.027). The initial symptoms were not different. There were no differences between the laboratory results of the groups. The ICU need was higher in the patients who do not use the drug than in the users (p<.020). Discussion(s): ACE/ARB usage in COVID-19 patients did not worsen the course of the disease. However, ACE/ARB users before COVID-19 pandemic were taken to ICU at a low rate.Copyright © 2022, Derman Medical Publishing. All rights reserved.
ABSTRACT
Background: Around 80% of patients who developed COVID-19-driven ARDS present lung ailment. There is a lack of knowledge of the mechanisms that mediate the pulmonary outcomes. Aim(s): To characterize the factors linked to diffusion impairment in survivors of severe COVID-19. Method(s): Prospective cohort study including 87 COVID-19-induced ARDS survivors. A complete pulmonary evaluation was performed 3 months after hospital discharge. 364 proteins were quantified using the proximity extension assay (PEA). Partial least square-discriminant analysis (PLS-DA) and random forest (RF) were used for multivariable analyses. Result(s): Moderate to severe diffusion impairment (DLCO<60% predicted) was observed in the 30% of the cohort. 15 proteins were differentially detected [false discovery rate (FDR)<0.05] in the univariate analysis. Pleiotrophin showed the highest differences (fold change=2.22 and FDR=0.001). In continuous analysis, proteins were inversely and independently associated with DLCO, and in some cases showed a robust dose-response relationship. PLS-DA and RF identified proteomic profiles related to the severity of diffusion capacity. Clusters identified were enriched in mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis. Proteins are expressed in immune and non-immune lung cells. Conclusion(s): In survivors of COVID-19-driven ARDS, lung dysfunction is linked to plasma factors involved in injury and repair mechanisms. The host proteomic profile provides a novel understanding of post-acute sequelae and may be source of therapeutic strategies and biomarkers.