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1.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574052

ABSTRACT

Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/administration & dosage , Interleukin-17/administration & dosage , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
2.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1505072

ABSTRACT

BACKGROUND: OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS: In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS: Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS: Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.

3.
Front Med (Lausanne) ; 7: 572989, 2020.
Article in English | MEDLINE | ID: covidwho-1488436

ABSTRACT

Background: The rapid coronavirus disease 2019 (COVID-19) pandemic has hit hard on the world and causes panic since the virus causes serious infectious respiratory illness and easily leads to severe conditions such as immune system overactivation or cytokine storm. Due to the limited knowledge on the course of infection of this coronavirus and the lack of an effective treatment for this fatal disease, mortality remains high. The emergence of a cytokine storm in patients with a severe condition has been reported as the top reason of the death of patients with COVID-19 infection. However, the causative mechanism of cytokine storm remains elusive. Thus, we aim to observe the association of coagulopathy (D-dimer) with cytokine (i.e., IL-6) and CT imaging in COVID-19-infected patients. Methods: In this retrospective observational study, we systematically analyzed the comprehensive clinical laboratory data of COVID-19-positive patients in different illness groups of mild, moderate, and severe conditions according to the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). T tests and chi-square tests were used for two-group comparisons. One-way ANOVA was used for three-group comparisons. Pearson and Spearman correlation coefficients of the D-dimer level with IL-6 and CT imaging were computed at baseline. With regular liquid biopsy approach, D-dimer, IL-6, and neutrophil-to-lymphocyte ratio were recorded repeatedly with a time curve to investigate disease progression, along with CT imaging, and other indicators. Results: All the 64 patients were clinically evaluated and classified into three groups of mild (32 cases), moderate (23 cases), and severe (nine cases) conditions. The D-dimer level positively correlated with IL-6 (R = 0.5) at baseline when the COVID-19-infected patients were admitted. In addition, we observed that D-dimer rises earlier than the cytokine storm represented by IL-6 surge, which suggests that coagulopathy might act as a trigger to potentiate a cytokine storm. Conclusion: Integrated analysis revealed a positive correlation of coagulopathy with cytokine storm in COVID-19-infected patients; the D-dimer rises early, which indicates that coagulopathy acts as a prodrome of cytokine storm. Coagulopathy can be used to monitor early cytokine storm in COVID-19-infected patients.

4.
Dev Neurosci ; 43(3-4): 143-158, 2021.
Article in English | MEDLINE | ID: covidwho-1472320

ABSTRACT

The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.

5.
Curr Pharm Des ; 27(33): 3566-3576, 2021.
Article in English | MEDLINE | ID: covidwho-1468275

ABSTRACT

BACKGROUND: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and re-emergence of human CoV outbreaks in the future. METHODS: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design. RESULTS: A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals' handlers to the infected animals, environmental changes, improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable conditions for "host switching" and the emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide a potential "molecular switch" for preferences of new host-receptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs. CONCLUSION: High propensity of mutations and "molecular adaptations" in coronaviruses creates the hot spots and high potential for "host switching", leading to the emergence of more virulent strains of human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for the emergence and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Animals , Humans , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
6.
Cochrane Database Syst Rev ; 6: CD013333, 2020 06 20.
Article in English | MEDLINE | ID: covidwho-1453528

ABSTRACT

BACKGROUND: Demodex blepharitis is a chronic condition commonly associated with recalcitrant dry eye symptoms though many people with Demodex mites are asymptomatic. The primary cause of this condition in humans is two types of Demodex mites: Demodex folliculorum and Demodex brevis. There are varying reports of the prevalence of Demodex blepharitis among adults, and it affects both men and women equally. While Demodex mites are commonly treated with tea tree oil, the effectiveness of tea tree oil for treating Demodex blepharitis is not well documented. OBJECTIVES: To evaluate the effects of tea tree oil on ocular Demodex infestation in people with Demodex blepharitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 6); Ovid MEDLINE; Embase.com; PubMed; LILACS; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no date or language restrictions in the electronic search for trials. We last searched the databases on 18 June 2019. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared treatment with tea tree oil (or its components) versus another treatment or no treatment for people with Demodex blepharitis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts and then full text of records to determine their eligibility. The review authors independently extracted data and assessed risk of bias using Covidence. A third review author resolved any conflicts at all stages. MAIN RESULTS: We included six RCTs (1124 eyes of 562 participants; 17 to 281 participants per study) from the US, Korea, China, Australia, Ireland, and Turkey. The RCTs compared some formulation of tea tree oil to another treatment or no treatment. Included participants were both men and women, ranging from 39 to 55 years of age. All RCTs were assessed at unclear or high risk of bias in one or more domains. We also identified two RCTs that are ongoing or awaiting publications. Data from three RCTs that reported a short-term mean change in the number of Demodex mites per eight eyelashes contributed to a meta-analysis. We are uncertain about the mean reduction for the groups that received the tea tree oil intervention (mean difference [MD] 0.70, 95% confidence interval [CI] 0.24 to 1.16) at four to six weeks as compared to other interventions. Only one RCT reported data for long-term changes, which found that the group that received intense pulse light as the treatment had complete eradication of Demodex mites at three months. We graded the certainty of the evidence for this outcome as very low. Three RCTs reported no evidence of a difference for participant reported symptoms measured on the Ocular Surface Disease Index (OSDI) between the tea tree oil group and the group receiving other forms of intervention. Mean differences in these studies ranged from -10.54 (95% CI - 24.19, 3.11) to 3.40 (95% CI -0.70 7.50). We did not conduct a meta-analysis for this outcome given substantial statistical heterogeneity and graded the certainty of the evidence as low. One RCT provided information concerning visual acuity but did not provide sufficient data for between-group comparisons. The authors noted that mean habitual LogMAR visual acuity for all study participants improved post-treatment (mean LogMAR 1.16, standard deviation 0.26 at 4 weeks). We graded the certainty of evidence for this outcome as low. No RCTs provided data on mean change in number of cylindrical dandruff or the proportion of participants experiencing conjunctival injection or experiencing meibomian gland dysfunction. Three RCTs provided information on adverse events. One reported no adverse events. The other two described a total of six participants randomized to treatment with tea tree oil who experienced ocular irritation or discomfort that resolved with re-educating the patient on application techniques and continuing use of the tea tree oil. We graded the certainty of the evidence for this outcome as very low. AUTHORS' CONCLUSIONS: The current review suggests that there is uncertainty related to the effectiveness of 5% to 50% tea tree oil for the short-term treatment of Demodex blepharitis; however, if used, lower concentrations may be preferable in the eye care arena to avoid induced ocular irritation. Future studies should be better controlled, assess outcomes at long term (e.g. 10 to 12 weeks or beyond), account for patient compliance, and study the effects of different tea tree oil concentrations.


Subject(s)
Anti-Infective Agents, Local/therapeutic use , Blepharitis/drug therapy , Mite Infestations/drug therapy , Tea Tree Oil/therapeutic use , Adult , Blepharitis/parasitology , Female , Humans , Male , Middle Aged , Mite Infestations/complications , Randomized Controlled Trials as Topic
7.
Hepatol Commun ; 2020 Aug 06.
Article in English | MEDLINE | ID: covidwho-1391569

ABSTRACT

Background and Aims: Previous studies reported that coronavirus disease 2019 (COVID-19) was likely to result in liver injury. However, few studies investigated liver injury in COVID-19 patients with chronic liver diseases. We described the clinical features in COVID-19 patients with non-alcoholic fatty liver disease (NAFLD). Methods: Confirmed COVID-19 patients from hospitals in 10 cities of Jiangsu province, China were retrospectively included between January 18, 2020, and February 26, 2020. Hepatic Steatosis Index (HSI) was used to defined NAFLD. Results: A total of 280 COVID-19 patients were enrolled. Eighty-six (30.7%) of 280 COVID-19 patients were diagnosed as NAFLD by HSI. 100 (35.7%) patients presented abnormal liver function on admission. The median ALT levels (34.5 U/L vs. 23.0 U/L, P<0.001) and the proportion of elevated ALT (>40 U/L) (40.7% vs. 10.8%, P<0.001) were significantly higher in patients with NAFLD than in patients without NAFLD on admission. The proportion of elevated ALT in patients with NAFLD was also significantly higher than patients without NAFLD (65.1% vs. 38.7%, P<0.001) during hospitalization. Multivariate analysis showed that age over 50 years (odds ratio [OR] 2.077, 95% confidence interval [CI] 1.183-3.648, P=0.011), and concurrent NAFLD (OR 2.956, 95% CI 1.526-5.726, P=0.001) were independent risk factors of ALT elevation in COVID-19 patients, while the atomized inhalation of interferon α-2b (OR 0.402, 95%CI 0.236-0.683, P=0.001) was associated with the reduced risk of ALT elevation during hospitalization. No patient developed liver failure or death during hospitalization. The complications and clinical outcomes were comparable between COVID-19 patients with and without NAFLD. Conclusions: NAFLD patients are more likely to develop liver injury when infected by COVID-19. However, no patient developed severe liver-related complications during hospitalization.

8.
ACS Omega ; 6(10): 7181-7185, 2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1387156

ABSTRACT

Serine proteases neutrophil elastase (NE), protease 3 (PR3), cathepsin G (CatG), and neutrophil serine protease 4 (NSP4) are released by activated neutrophils swarming around the place of pathogen invasion to provoke an immune response. However, uncontrolled proteolytic activity of proteases results in various human diseases, including cardiovascular diseases, thrombosis, and autoimmunity. In addition, proteases can be hijacked by several viruses to prime virus-derived surface proteins and evade immune detection by entering into the host cell. Indeed, porcine elastase increases the suitability of host cells to be infected by SARS-CoV-1. We compared the cleavage sites of human NE, PR3, and CatG as well as porcine-derived trypsin within the amino acid sequence of the proteolytic sensitive activation loop at the interface of S1/S2 of the spike protein (S protein) of SARS-CoV-1 as well as SARS-CoV-2. As a result, NE and PR3, but not CatG, hydrolyze the scissile peptide bond adjacent to the polybasic amino acid sequence of the S1/S2 interface of SARS-CoV-2, which is distinctive from SARS-CoV-1. These findings suggest that neutrophil-derived NE and PR3 participate in priming of the S1/S2 interface during an immune response.

9.
Cytokine ; 140: 155430, 2021 04.
Article in English | MEDLINE | ID: covidwho-1385381

ABSTRACT

In vitro interferon (IFN)α treatment of primary human upper airway basal cells has been shown to drive ACE2 expression, the receptor of SARS-CoV-2. The protease furin is also involved in mediating SARS-CoV-2 and other viral infections, although its association with early IFN response has not been evaluated yet. In order to assess the in vivo relationship between ACE2 and furin expression and the IFN response in nasopharyngeal cells, we first examined ACE2 and furin levels and their correlation with the well-known marker of IFNs' activation, ISG15, in children (n = 59) and adults (n = 48), during respiratory diseases not caused by SARS-CoV-2. A strong positive correlation was found between ACE2 expression, but not of furin, and ISG15 in all patients analyzed. In addition, type I and III IFN stimulation experiments were performed to examine the IFN-mediated activation of ACE2 isoforms (full-length and truncated) and furin in epithelial cell lines. Following all the IFNs treatments, only the truncated ACE2 levels, were upregulated significantly in the A549 and Calu3 cells, in particular by type I IFNs. If confirmed in vivo following IFNs' activation, the induction of the truncated ACE2 isoform only would not enhance the risk of SARS-CoV-2 infection in the respiratory tract.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/prevention & control , Epithelial Cells/drug effects , Gene Expression/drug effects , Interferons/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adult , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/virology , Cell Line, Tumor , Child , Cytokines/genetics , Epithelial Cells/metabolism , Humans , Interferons/metabolism , Lung/cytology , Middle Aged , SARS-CoV-2/physiology , Ubiquitins/genetics
10.
Viruses ; 13(1)2020 12 30.
Article in English | MEDLINE | ID: covidwho-1389523

ABSTRACT

SARS-CoV-2 is highly pathogenic in humans and poses a great threat to public health worldwide. Clinical data shows a disturbed type I interferon (IFN) response during the virus infection. In this study, we discovered that the nucleocapsid (N) protein of SARS-CoV-2 plays an important role in the inhibition of interferon beta (IFN-ß) production. N protein repressed IFN-ß production induced by poly(I:C) or upon Sendai virus (SeV) infection. We noted that N protein also suppressed IFN-ß production, induced by several signaling molecules downstream of the retinoic acid-inducible gene I (RIG-I) pathway, which is the crucial pattern recognition receptor (PRR) responsible for identifying RNA viruses. Moreover, our data demonstrated that N protein interacted with the RIG-I protein through the DExD/H domain, which has ATPase activity and plays an important role in the binding of immunostimulatory RNAs. These results suggested that SARS-CoV-2 N protein suppresses the IFN-ß response through targeting the initial step, potentially the cellular PRR-RNA-recognition step in the innate immune pathway. Therefore, we propose that the SARS-CoV-2 N protein represses IFN-ß production by interfering with RIG-I.


Subject(s)
COVID-19/immunology , DEAD Box Protein 58/metabolism , Interferon-beta/metabolism , Nucleocapsid Proteins/metabolism , SARS-CoV-2/metabolism , A549 Cells , Animals , DEAD Box Protein 58/genetics , HEK293 Cells , HeLa Cells , Host-Pathogen Interactions/immunology , Humans , Protein Interaction Domains and Motifs , Receptors, Immunologic , Signal Transduction
11.
Molecules ; 25(21)2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-1389462

ABSTRACT

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Plant Extracts/therapeutic use , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Air Sacs/drug effects , Air Sacs/virology , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , COVID-19 , Chromatography, High Pressure Liquid/methods , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Disease Models, Animal , Fever/drug therapy , Fever/etiology , Hemorrhage/prevention & control , Humans , Interleukin-6/metabolism , Kidney/drug effects , Necrosis/pathology , Necrosis/prevention & control , Pandemics , Phytotherapy , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiratory Mucosa/transplantation , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/metabolism , Zebrafish
12.
JCI Insight ; 6(13)2021 06 18.
Article in English | MEDLINE | ID: covidwho-1346128

ABSTRACT

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.


Subject(s)
Arthritis, Rheumatoid/immunology , COVID-19/immunology , Monocytes/immunology , Neutrophils/immunology , Osteopontin/immunology , Arthritis, Rheumatoid/metabolism , B7-H1 Antigen/immunology , Bronchoalveolar Lavage Fluid/immunology , CD48 Antigen/immunology , COVID-19/chemically induced , COVID-19/metabolism , Fatty Acid-Binding Proteins/immunology , Humans , Lectins/immunology , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Lung/diagnostic imaging , Lung/immunology , Lung/metabolism , Lung/pathology , Macrophages/immunology , Macrophages/metabolism , Membrane Glycoproteins/immunology , Monocytes/metabolism , Neutrophils/metabolism , Osteopontin/blood , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Immunologic/immunology , S100A12 Protein/immunology , S100A12 Protein/metabolism , Synovial Membrane/immunology , Tomography, X-Ray Computed
13.
Brief Bioinform ; 22(2): 1466-1475, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343667

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.


Subject(s)
COVID-19/virology , Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/blood , SARS-CoV-2/metabolism , Adult , Autophagy , Biomarkers/blood , COVID-19/blood , Cell Cycle , Cholesterol/metabolism , Female , Humans , Male , Middle Aged , RNA-Binding Proteins/blood , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
14.
Biomolecules ; 11(5)2021 04 29.
Article in English | MEDLINE | ID: covidwho-1334991

ABSTRACT

The vascular endothelium acts as a selective barrier to regulate macromolecule exchange between the blood and tissues. However, the integrity of the endothelium barrier is compromised in an array of pathological settings, including ischemic disease and cancer, which are the leading causes of death worldwide. The resulting vascular hyperpermeability to plasma molecules as well as leukocytes then leads to tissue damaging edema formation and inflammation. The vascular endothelial growth factor A (VEGFA) is a potent permeability factor, and therefore a desirable target for impeding vascular hyperpermeability. However, VEGFA also promotes angiogenesis, the growth of new blood vessels, which is required for reperfusion of ischemic tissues. Moreover, edema increases interstitial pressure in poorly perfused tumors, thereby affecting the delivery of therapeutics, which could be counteracted by stimulating the growth of new functional blood vessels. Thus, targets must be identified to accurately modulate the barrier function of blood vessels without affecting angiogenesis, as well as to develop more effective pro- or anti-angiogenic therapies. Recent studies have shown that the VEGFA co-receptor neuropilin 1 (NRP1) could be playing a fundamental role in steering VEGFA-induced responses of vascular endothelial cells towards angiogenesis or vascular permeability. Moreover, NRP1 is involved in mediating permeability signals induced by ligands other than VEGFA. This review therefore focuses on current knowledge on the role of NRP1 in the regulation of vascular permeability signaling in the endothelium to provide an up-to-date landscape of the current knowledge in this field.


Subject(s)
Capillary Permeability , Endothelium, Vascular/metabolism , Neuropilin-1/metabolism , Animals , Gene Expression Regulation , Humans , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism
15.
J Parkinsons Dis ; 11(s1): S11-S18, 2021.
Article in English | MEDLINE | ID: covidwho-1318376

ABSTRACT

Telemedicine programs are particularly suited to evaluating patients with Parkinson's disease (PD) and other movement disorders, primarily because much of the physical exam findings are visual. Telemedicine uses information and communication technologies to overcome geographical barriers and increase access to healthcare service. It is particularly beneficial for rural and underserved communities, groups that traditionally suffer from lack of access to healthcare. There is a growing evidence of the feasibility of telemedicine, cost and time savings, patients' and physicians' satisfaction, and its outcome and impact on patients' morbidity and quality of life. In addition, given the unusual current situation with the COVID-19 pandemic, telemedicine has offered the opportunity to address the ongoing healthcare needs of patients with PD, to reduce in-person clinic visits, and human exposures (among healthcare workers and patients) to a range of infectious diseases including COVID-19. However, there are still several challenges to widespread implementation of telemedicine including the limited performance of parts of the neurological exam, limited technological savvy, fear of loss of a personal connection, or uneasiness about communicating sensitive information. On the other hand, while we are facing the new wave of COVID-19 pandemic, patients and clinicians are gaining increasing experience with telemedicine, facilitating equity of access to specialized multidisciplinary care for PD. This article summarizes and reviews the current state and future directions of telemedicine from a global perspective.


Subject(s)
Parkinson Disease/diagnosis , Parkinson Disease/therapy , Telemedicine , COVID-19/complications , Health Services Accessibility , Humans , Pandemics
16.
J Clin Pathol ; 74(8): 528-532, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1318062

ABSTRACT

AIMS: Brazil is nowadays one of the epicentres of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and new therapies are needed to face it. In the context of specific immune response against the virus, a correlation between Major Histocompatibility Complex Class I (MHC-I) and the severity of the disease in patients with COVID-19 has been suggested. Aiming at better understanding the biology of the infection and the immune response against the virus in the Brazilian population, we analysed SARS-CoV-2 protein S peptides in order to identify epitopes able to elicit an immune response mediated by the most frequent MHC-I alleles using in silico methods. METHODS: Our analyses consisted in searching for the most frequent Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-C alleles in the Brazilian population, excluding the genetic isolates; then, we performed: molecular modelling for unsolved structures, MHC-I binding affinity and antigenicity prediction, peptide docking and molecular dynamics of the best fitted MHC-I/protein S complexes. RESULTS: We identified 24 immunogenic epitopes in the SARS-CoV-2 protein S that could interact with 17 different MHC-I alleles (namely, HLA-A*01:01; HLA-A*02:01; HLA-A*11:01; HLA-A*24:02; HLA-A*68:01; HLA-A*23:01; HLA-A*26:01; HLA-A*30:02; HLA-A*31:01; HLA-B*07:02; HLA-B*51:01; HLA-B*35:01; HLA-B*44:02; HLA-B*35:03; HLA-C*05:01; HLA-C*07:01 and HLA-C*15:02) in the Brazilian population. CONCLUSIONS: Being aware of the intrinsic limitations of in silico analysis (mainly the differences between the real and the Protein Data Bank (PDB) structure; and accuracy of the methods for simulate proteasome cleavage), we identified 24 epitopes able to interact with 17 MHC-I more frequent alleles in the Brazilian population that could be useful for the development of strategic methods for vaccines against SARS-CoV-2.


Subject(s)
Epitope Mapping , Epitopes , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Brazil , Gene Frequency , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , SARS-CoV-2/pathogenicity
17.
Biomolecules ; 11(5)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1299401

ABSTRACT

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells-a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.


Subject(s)
Arachidonate 12-Lipoxygenase/metabolism , Inflammation/immunology , Metabolic Diseases/immunology , Animals , Arachidonate 12-Lipoxygenase/genetics , Humans , Inflammation/metabolism , Inflammation/pathology , Lipid Metabolism , Metabolic Diseases/metabolism , Metabolic Diseases/pathology , Oxidation-Reduction
18.
J Clin Immunol ; 41(5): 914-922, 2021 07.
Article in English | MEDLINE | ID: covidwho-1293410

ABSTRACT

BACKGROUND: In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta. OBJECTIVES: We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes. METHODS: We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain. RESULTS: The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%), while they were not found in any of the 118 asymptomatic controls (p = 0.0016). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p = 5.10e-03) and lower lymphocyte counts (p = 1.80e-02). No significant association with response to IFN-beta-1b therapy (p = 0.34) was found. Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%). CONCLUSION: Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.


Subject(s)
Antibodies, Neutralizing/blood , Autoantibodies/blood , COVID-19/immunology , Interferon Type I/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , C-Reactive Protein/analysis , Female , Hospitalization , Humans , Male , Middle Aged
19.
J Transl Med ; 19(1): 232, 2021 05 31.
Article in English | MEDLINE | ID: covidwho-1280593

ABSTRACT

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients. METHODS: NIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy. DISCUSSION: Checkpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1 .


Subject(s)
Mesothelioma, Malignant , Mesothelioma , Antineoplastic Combined Chemotherapy Protocols , Humans , Ipilimumab/therapeutic use , Mesothelioma/drug therapy , Nivolumab/therapeutic use , Vaccination
20.
J Cell Mol Med ; 25(14): 7001-7012, 2021 07.
Article in English | MEDLINE | ID: covidwho-1276684

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in many deaths throughout the world. It is vital to identify the novel prognostic biomarkers and therapeutic targets to assist with the subsequent diagnosis and treatment plan to mitigate the expansion of COVID-19. Since angiotensin-converting enzyme 2 (ACE2)-positive cells are hosts for COVID-19, we focussed on this cell type to explore the underlying mechanisms of COVID-19. In this study, we identified that ACE2-positive cells from the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 belong to bronchial epithelial cells. Comparing with patients of COVID-19 showing severe symptoms, the antigen processing and presentation pathway was increased and 12 typical genes, HLA-DRB5, HLA-DRB1, CD74, HLA-DRA, HLA-DPA1, HLA-DQA1, HSP90AA1, HSP90AB1, HLA-DPB1, HLA-DQB1, HLA-DQA2, and HLA-DMA, particularly HLA-DPB1, were obviously up-regulated in ACE2-positive bronchial epithelial cells of patients with mild disease. We further discovered SDCBP was positively correlated with above 12 genes particularly with HLA-DPB1 in ACE2-positive bronchial epithelial cells of COVID-19 patients. Moreover, SDCBP may increase the immune infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in different lung carcinoma. Moreover, we found the expression of SDCBP was positively correlated with the expression of antigen processing and presentation genes in post-mortem lung biopsies tissues, which is consistent with previous discoveries. These results suggest that SDCBP has good potential to be further developed as a novel diagnostic and therapeutic target in the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Bronchi/pathology , COVID-19/pathology , Epithelial Cells/metabolism , RNA-Seq , Severity of Illness Index , Single-Cell Analysis , Syntenins/metabolism , Antigen Presentation/genetics , Bronchoalveolar Lavage Fluid , COVID-19/genetics , COVID-19/metabolism , Epithelial Cells/pathology , Gene Expression Profiling , Humans , Postmortem Changes , SARS-CoV-2/physiology , Up-Regulation/genetics
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