Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: April 12, 2021

Abstract COVID-19 is a respiratory illness caused by novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10–15-fold higher affinity compared SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter susceptibility SARS-CoV-2 affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple protein-altering variants. Using reported structural data, natural variants that could potentially affect virus–host interaction thereby susceptibility. These include S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P H378R were predicted increase susceptibility, while K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L D509Y be protective show decreased binding S-protein. biochemical assays, confirmed K31R E37K had affinity, K26R T92I showed increased for S-protein when wildtype ACE2. Consistent this, soluble more effective in blocking entry of pseudotyped virus suggesting modulate

Language: Английский

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SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

PLoS Pathogens, Journal Year: 2021, Volume and Issue: 17(2), P. e1009225 - e1009225

Published: Feb. 17, 2021

Since the initial report of novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has spread globally. While effects SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum disease ranging mild symptoms severe respiratory distress, hospitalization, and mortality. There no Food Drug Administration (FDA)-approved treatments for COVID-19 aside remdesivir; early efforts identify efficacious therapeutics have mainly focused on drug repurposing screens compounds with antiviral activity against in cellular systems. These yielded intriguing hits, but use nonhuman immortalized cell lines derived non-pulmonary or gastrointestinal origins poses any number questions predicting physiological pathological relevance these potential interventions. our knowledge this virus continues evolve, current understanding key molecular interactions involved is discussed order provide framework developing most appropriate vitro toolbox support future discovery efforts.

Language: Английский

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Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics

Frontiers in Cellular and Infection Microbiology, Journal Year: 2020, Volume and Issue: 10

Published: Dec. 8, 2020

The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by robust immunological response leading to ARDS multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome 2 (SARS-CoV-2) COVID-19 from different points view. CatL lysosomal enzyme that participates numerous physiological processes, including apoptosis, antigen processing, extracellular matrix remodeling. implicated pathological conditions like invasion metastasis tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, other diseases. expression up-regulated during chronic inflammation involved degrading matrix, an important process SARS-CoV-2 enter host cells. In addition, probably processing spike protein. As its inhibition detrimental infection possibly exit cells late stages could have been considered valuable therapeutic target. Therefore, describe here some drugs already market potential inhibiting capacity be used treat patients. discuss possible role genetics etiology spreading disease.

Language: Английский

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The influence of HLA genotype on the severity of COVID‐19 infection

HLA, Journal Year: 2021, Volume and Issue: 98(1), P. 14 - 22

Published: April 25, 2021

The impact of COVID-19 varies markedly, not only between individual patients but also different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might influence this variation. Using next generation sequencing, we analysed the class I and II classical HLA 147 individuals European descent experiencing variable clinical outcomes following infection. Forty-nine these were admitted to hospital with severe respiratory disease. They had no significant pre-existing comorbidities. compared results those obtained from a group 69 asymptomatic workers who evidence COVID exposure based on blood antibody testing. Allele frequencies both groups local national healthy controls adjustments made for age sex. With inclusion staff reported localised symptoms (limited loss smell/taste, n = 13) or systemic requiring treatment (n 16), carried out ordinal logistic regression modelling determine relative age, BMI, sex presence specific symptomatology. found difference allele frequency HLA-DRB1*04:01 patient (5.1% vs. 16.7%, P .003 after adjustment sex). There was significantly lower haplotype DQA1*01:01-DQB1*05:01-DRB1*01:01 background population (P .007). Ordinal confirmed DRB1*04:01 severity observed cohorts. These alleles are greater North Western population. This regional study provides genotype influences outcome Validation studies must take account complex genetic architecture immune system across geographies ethnicities.

Language: Английский

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Epidemiology of Brain and Other CNS Tumors

Current Neurology and Neuroscience Reports, Journal Year: 2021, Volume and Issue: 21(12)

Published: Nov. 24, 2021

Abstract Purpose of Review Brain and other central nervous system (CNS) tumors, while rare, cause significant morbidity mortality across all ages. This article summarizes the current state knowledge on epidemiology brain CNS tumors. Recent Findings For childhood adolescent high birth weight, non-chromosomal structural defects higher socioeconomic position were shown to be risk factors. adults, increased leukocyte telomere length, proportion European ancestry, position, HLA haplotypes increase malignant immune factors decrease risk. Summary Although no factor accounting for a large tumors has been discovered, use throughput “omics” approaches improved detection/measurement environmental exposures will help us refine our understanding these discover novel this disease.

Language: Английский

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Genetically adjusted PSA levels for prostate cancer screening

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(6), P. 1412 - 1423

Published: June 1, 2023

Abstract Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting genetic determinants constitutive, non-cancer-related PSA variation has potential to improve utility. In this study, we discovered 128 genome-wide significant associations ( P < 5 × 10 −8 ) in a multi-ancestry meta-analysis 95,768 men developed polygenic score (PGS that explains 9.61% constitutive variation. We found that, European ancestry, using PGS-adjusted would avoid up 31% negative biopsies but also result 12% fewer patients with cancer, mostly Gleason <7 Genetically adjusted was more predictive aggressive (odds ratio (OR) = 3.44, 6.2 −14 , area under the curve (AUC) 0.755) than unadjusted (OR 3.31, 1.1 −12 AUC 0.738) 106 cases 23,667 controls. Compared PGS alone (AUC 0.712), including genetically improved detection disease 0.786, 7.2 −4 ). Our findings highlight utility incorporating personalized biomarkers screening.

Language: Английский

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ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease

Microbial Pathogenesis, Journal Year: 2020, Volume and Issue: 150, P. 104621 - 104621

Published: Dec. 2, 2020

Language: Английский

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Association between HLA genotypes and COVID-19 susceptibility, severity and progression: a comprehensive review of the literature

European journal of medical research, Journal Year: 2021, Volume and Issue: 26(1)

Published: Aug. 3, 2021

The COVID-19 pandemic has markedly impacted on cultural, political, and economic structures all over the world. Several aspects of its pathogenesis related clinical consequences have not yet been elucidated. Infection rates, as well morbidity mortality differed within countries. It is intriguing for scientists to understand how patient genetics may influence outcome condition, clarify which could be variability SARS-CoV-2 disease. We reviewed studies exploring role human leukocyte antigens (HLA) genotypes individual responses infection and/or progression, discussing also contribution immunological patterns MHC-related. In March 2021, main online databases were accessed. All articles that investigated possible association between HLA polymorphisms with susceptibility, severity progression considered. Although both genetic environmental factors are certainly expected susceptibility or protection individuals, can infection. crucial played by molecules in immune response, especially through pathogen-derived peptide presentation, huge molecular alleles populations responsible different rates patients following

Language: Английский

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COVID-19: Understanding Inter-Individual Variability and Implications for Precision Medicine

Mayo Clinic Proceedings, Journal Year: 2020, Volume and Issue: 96(2), P. 446 - 463

Published: Dec. 3, 2020

Language: Английский

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First flare of ACPA-positive rheumatoid arthritis after SARS-CoV-2 infection

The Lancet Rheumatology, Journal Year: 2020, Volume and Issue: 3(1), P. e6 - e8

Published: Nov. 24, 2020

Language: Английский

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