Mast cells: Therapeutic targets for COVID-19 and beyond.
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ABSTRACT:
SUBMITTER: Lam HY
PROVIDER: S-EPMC8652840 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Beginning in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a novel pathogen that causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 has infected more than 111 million people worldwide and caused over 2.47 million deaths. Individuals infected with SARS-CoV-2 show symptoms of fever, cough, dyspnea, and fatigue with severe cases that can develop into pneumonia, myocarditis, acute respiratory distress syndrome, hypercoagulability, and even multi-organ failure. Current clinical management consists largely of supportive care as commonly administered treatments, including convalescent plasma, remdesivir, and high-dose glucocorticoids. These have demonstrated modest benefits in a small subset of hospitalized patients, with only dexamethasone showing demonstrable efficacy in reducing mortality and length of hospitalization. At this time, no SARS-CoV-2-specific antiviral drugs are available, although several vaccines have been approved for use in recent months. In this review, we will evaluate the efficacy of preclinical and clinical drugs that precisely target three different, essential steps of the SARS-CoV-2 replication cycle: the spike protein during entry, main protease (MPro) during proteolytic activation, and RNA-dependent RNA polymerase (RdRp) during transcription. We will assess the advantages and limitations of drugs that precisely target evolutionarily well-conserved domains, which are less likely to mutate, and therefore less likely to escape the effects of these drugs. We propose that a multi-drug cocktail targeting precise proteins, critical to the viral replication cycle, such as spike protein, MPro, and RdRp, will be the most effective strategy of inhibiting SARS-CoV-2 replication and limiting its spread in the general population.
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Project description:The global pandemic COVID-19, caused by novel coronavirus SARS-CoV-2, has emerged as severe public health issue crippling world health care systems. Substantial knowledge has been generated about the pathophysiology of the disease and possible treatment modalities in a relatively short span of time. As of August 19, 2020, there is no approved drug for the treatment of COVID-19. More than 600 clinical trials for potential therapeutics are underway and the results are expected soon. Based on early experience, different treatment such as anti-viral drugs (remdesivir, favipiravir, lopinavir/ritonavir), corticosteroids (methylprednisolone, dexamethasone) or convalescent plasma therapy are recommended in addition to supportive care and symptomatic therapy. There are several treatments currently being investigated to address the pathological conditions associated with COVID-19. This review provides currently available information and insight into pathophysiology of the disease, potential targets, and relevant clinical trials for COVID-19.
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Project description:SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H 2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.
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Project description:SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.
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Project description:The inflammatory response to severe acute respiratory syndrome-related coronavirus 2 infection has a direct impact on the clinical outcomes of coronavirus disease 2019 patients. Of the many innate immune pathways that are engaged by severe acute respiratory syndrome-related coronavirus 2, we highlight the importance of the inflammasome pathway. We discuss available pharmaceutical agents that target a critical component of inflammasome activation, signaling leading to cellular pyroptosis, and the downstream cytokines as a promising target for the treatment of severe coronavirus disease 2019-associated diseases.
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Project description:The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren's syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still's disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Points• Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.• Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.• Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.
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Project description:Whilst the majority of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, experience mild to moderate symptoms, approximately 20% develop severe respiratory complications that may progress to acute respiratory distress syndrome, pulmonary failure and death. To date, single cell and high-throughput systems based analyses of the peripheral and pulmonary immune responses to SARS-CoV-2 suggest that a hyperactive and dysregulated immune response underpins the development of severe disease, with a prominent role assigned to neutrophils. Characterised in part by robust generation of neutrophil extracellular traps (NETs), the presence of immature, immunosuppressive and activated neutrophil subsets in the circulation, and neutrophilic infiltrates in the lung, a granulocytic signature is emerging as a defining feature of severe COVID-19. Furthermore, an assessment of the number, maturity status and/or function of circulating neutrophils at the time of hospital admission has shown promise as a prognostic tool for the early identification of patients at risk of clinical deterioration. Here, by summarising the results of studies that have examined the peripheral and pulmonary immune response to SARS-CoV-2, we provide a comprehensive overview of the changes that occur in the composition, phenotype and function of the neutrophil pool in COVID-19 patients of differing disease severities and discuss potential mediators of SARS-CoV-2-induced neutrophil dysfunction. With few specific treatments currently approved for COVID-19, we conclude the review by discussing whether neutrophils represent a potential therapeutic target for the treatment of patients with severe COVID-19.
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Project description:The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.
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Project description:Telomeres, the repetitive sequences at chromosomal ends, protect intact chromosomes. Telomeres progressively shorten through successive rounds of cell divisions, and critically shortened telomeres trigger senescence and apoptosis. The enzyme that elongates telomeres and maintains their structure is known as telomerase. The catalytic subunit of this enzyme (telomerase reverse transcriptase [TERT]) is expressed at a high level in malignant cells, but at a very low level in normal cells. Although telomerase activity was long believed to be the only function of TERT, emerging evidence indicates that TERT plays roles beyond telomeres. For example, TERT contributes to stem cell maintenance and cell reprogramming processes in a manner independent of its canonical function. Even some types of splice variants that lack the telomerase catalytic domains exhibit the functions in a manner that does not depend on telomerase activity. We recently demonstrated that the RNA-dependent RNA polymerase (RdRP) activity of TERT is involved in regulation of gene silencing and heterochromatic transcription. Moreover, TERT RdRP activity is mediated by a newly identified complex, distinct from the authentic telomerase complex, that plays a role in cancer stem cells in a telomere maintenance independent manner. TERT has attracted interest as a molecular target for anticancer treatment, but previous efforts aimed at developing novel therapeutic strategies focused only on the canonical function of TERT. However, accumulating evidence about the non-canonical functions of TERT led us to speculate that the functions other than telomerase might be therapeutic targets as well. In this review, we discuss the non-canonical functions of TERT and their potential applications for anticancer treatment.
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Project description:The ongoing episode of coronavirus disease 19 (COVID-19) has imposed a serious threat to global health and the world economy. The disease has rapidly acquired a pandemic status affecting almost all populated areas of the planet. The causative agent of COVID-19 is a novel coronavirus known as SARS-CoV-2. The virus has an approximate 30 kb single-stranded positive-sense RNA genome, which is 74.5% to 99% identical to that of SARS-CoV, CoV-pangolin, and the coronavirus the from horseshoe bat. According to available information, SARS-CoV-2 is inferred to be a recombinant virus that originated from bats and was transmitted to humans, possibly using the pangolin as the intermediate host. The interaction of the SARS-CoV-2 spike protein with the human ACE2 (angiotensin-converting enzyme 2) receptor, and its subsequent cleavage by serine protease and fusion, are the main events in the pathophysiology. The serine protease inhibitors, spike protein-based vaccines, or ACE2 blockers may have therapeutic potential in the near future. At present, no vaccine is available against COVID-19. The disease is being treated with antiviral, antimalarial, anti-inflammatory, herbal medicines, and active plasma antibodies. In this context, the present review article provides a cumulative account of the recent information regarding the viral characteristics, potential therapeutic targets, treatment options, and prospective research questions.
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