Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Alpha-1-antitrypsin: A possible host protective factor against Covid-19.

ABSTRACT: Understanding Covid-19 pathophysiology is crucial for a better understanding of the disease and development of more effective treatments. Alpha-1-antitrypsin (A1AT) is a constitutive tissue protector with antiviral and anti-inflammatory properties. A1AT inhibits SARS-CoV-2 infection and two of the most important proteases in the pathophysiology of Covid-19: the transmembrane serine protease 2 (TMPRSS2) and the disintegrin and metalloproteinase 17 (ADAM17). It also inhibits the activity of inflammatory molecules, such as IL-8, TNF-α, and neutrophil elastase (NE). TMPRSS2 is essential for SARS-CoV-2-S protein priming and viral infection. ADAM17 mediates ACE2, IL-6R, and TNF-α shedding. ACE2 is the SARS-CoV-2 entry receptor and a key component for the balance of the renin-angiotensin system, inflammation, vascular permeability, and pulmonary homeostasis. In addition, clinical findings indicate that A1AT levels might be important in defining Covid-19 outcomes, potentially partially explaining associations with air pollution and with diabetes. In this review, we focused on the interplay between A1AT with TMPRSS2, ADAM17 and immune molecules, and the role of A1AT in the pathophysiology of Covid-19, opening new avenues for investigating effective treatments.

SUBMITTER: de Loyola MB

PROVIDER: S-EPMC7461031 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Host genomics of COVID-19: Evidence point towards Alpha 1 antitrypsin deficiency as a putative risk factor for higher mortality rate.

Project description:Corona Virus Disease 2019 (COVID-19) has emerged as a pandemic leading to unprecedented disruption of global health and economy. Transmembrane protease serine 2 (TMPRSS2) has been found to be critical in priming the viral spike protein and the host ACE2 receptor before the virus enters into the host cell. Recent studies have experimentally demonstrated that Alpha 1 antitrypsin (encoded by SERPINA1 gene) is an inhibitor of TMPRSS2 and provided support to the already approved therapy as a candidate for COVID-19. Interestingly Alpha 1 antitrypsin deficiency is common among Europeans. Here we have provided in silico evidence that Alpha 1 antitrypsin can interact with TMPRSS2 and both of them are co-expressed in the human liver and lung. We then analyzed the gnomAD dataset to show that Europeans and Latinos have a substantially higher carrier frequency of Alpha 1 Antitrypsin Deficiency (~12%) compared to other large ethnicities. Therefore, we hypothesize that Alpha 1 antitrypsin deficiency might be a risk factor for severe infection with SARS-CoV-2. We propose Alpha 1 antitrypsin status as a potential prognostic predictor of COVID-19 outcome.

| S-EPMC7796667 | biostudies-literature

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19.

Project description:The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin-TMPRSS2-AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2-AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.

| S-EPMC8953970 | biostudies-literature

Therapeutic Application of Alpha-1 Antitrypsin in COVID-19.

Project description: Not available

| S-EPMC8650782 | biostudies-literature

Alpha-1 antitrypsin for cystic fibrosis complicated by severe cytokinemic COVID-19.

Project description:BackgroundThe clinical course of severe COVID-19 in cystic fibrosis (CF) is incompletely understood. We describe the use of alpha-1 antitrypsin (AAT) as a salvage therapy in a critically unwell patient with CF (PWCF) who developed COVID-19 while awaiting lung transplantation.MethodsIV AAT was administered at 120 mg/kg/week for 4 consecutive weeks. Levels of interleukin (IL)-1β, IL-6, IL-8, and soluble TNF receptor 1 (sTNFR1) were assessed at regular intervals in plasma, with IL-1β, IL-6, IL-8 and neutrophil elastase (NE) activity measured in airway secretions. Levels were compared to baseline and historic severe exacerbation measurements.ResultsSystemic and airway inflammatory markers were increased compared to both prior exacerbation and baseline levels, in particular IL-6, IL-1β and NE activity. Following each AAT dose, rapid decreases in each inflammatory parameter were observed. These were matched by marked clinical and radiographic improvement.ConclusionsThe results support further investigation of AAT as a COVID-19 therapeutic, and re-exploration of its use in CF.

| S-EPMC7678455 | biostudies-literature

Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis.

Project description:RationaleSARS-CoV-2 entry into host cells is facilitated by endogenous and exogenous proteases that proteolytically activate the spike glycoprotein and antiproteases inhibiting this process. Understanding the key actors in viral entry is crucial for advancing knowledge of virus tropism, pathogenesis, and potential therapeutic targets.ObjectivesWe aimed to investigate the role of naïve serum and alpha-1-antitrypsin (AAT) in inhibiting protease-mediated SARS-CoV-2 entry and explore the implications of AAT deficiency on susceptibility to different SARS-CoV-2 variants.FindingsOur study demonstrates that naïve serum exhibits significant inhibition of SARS-CoV-2 entry, with AAT identified as the major serum protease inhibitor potently restricting entry. Using pseudoparticles, replication-competent pseudoviruses, and authentic SARS-CoV-2, we show that AAT inhibition occurs at low concentrations compared with those in serum and bronchoalveolar tissues, suggesting physiological relevance. Furthermore, sera from subjects with an AAT-deficient genotype show reduced ability to inhibit entry of both Wuhan-Hu-1 (WT) and B.1.617.2 (Delta) but exhibit no difference in inhibiting B.1.1.529 (Omicron) entry.ConclusionsAAT may have a variant-dependent therapeutic potential against SARS-CoV-2. Our findings highlight the importance of further investigating the complex interplay between proteases, antiproteases, and spike glycoprotein activation in SARS-CoV-2 and other respiratory viruses to identify potential therapeutic targets and improve understanding of disease pathogenesis.

| S-EPMC7430570 | biostudies-literature

Protective potential of expectorants against COVID-19.

Project description: Not available

| S-EPMC7229712 | biostudies-literature

Possible Therapeutic Use of Natural Compounds Against COVID-19.

Project description:The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that has resulted in devastating social, economic, morbidity and mortality burdens. SARS-CoV-2 infects cells following receptor-mediated endocytosis and priming by cellular proteases. Following uptake, SARS-CoV-2 replicates in autophagosome-like structures in the cytosol following its escape from endolysosomes. Accordingly, the greater endolysosome pathway including autophagosomes and the mTOR sensor may be targets for therapeutic interventions against SARS-CoV-2 infection and COVID-19 pathogenesis. Naturally existing compounds (phytochemicals) through their actions on endolysosomes and mTOR signaling pathways might provide therapeutic relief against COVID-19. Here, we discuss evidence that some natural compounds through actions on the greater endolysosome system can inhibit SARS-CoV-2 infectivity and thereby might be repurposed for use against COVID-19.

| S-EPMC7990267 | biostudies-literature

Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants

Project description:COVID-19 has infected 244 million people globally and evolved several variants with higher infectivity. Drug repurposing could be an efficient and timely means of drug discovery for the pandemic. To date, more than two hundred repurposed SARS-CoV-2 inhibitors have been reported but with moderate efficacy or acute toxicity. Thus, there is a great need to find new effective candidates against SARS-CoV-2, especially the new variants, with good safety profiles. We analyzed 17 hundred published host RNA-seq samples of SARS/MERS/SARS-CoV-2 infection derived from pre-clinical models or patients, together with the reported coronavirus inhibitors to summarize a robust coronavirus-induced host gene expression change signature, which captured biological processes involved in host cell machinery hijacking and immune evasion. Then we searched for drugs potently reversing the infection signature and discovered IMD-0354 as a promising candidate with nanomolar IC50 against SARS-CoV-2 and 6 variants, showing a wide therapeutic window of more than 100-fold. The RNA-seq of IMD-0354 treated cells infected with SARS-CoV-2 reaved that this drug could stimulate type I interferon antiviral response, inhibit viral entry and down-regulate hijacked proteins. This work demonstrated the power of biological big data and the efficiency of a system-based drug discovery approach, which can be used in future pandemic.

2022-02-28 | GSE187420 | GEO

Alpha-1 Antitrypsin for COVID-19 Treatment: Dual Role in Antiviral Infection and Anti-Inflammation.

Project description:Many drugs have been approved for clinical trials for the treatment of COVID-19 disease, focusing on either antiviral or anti-inflammatory approaches. Combining antiviral and anti-inflammatory drugs or therapies together may be more effective. Human alpha-1 antitrypsin (A1AT) is a blood circulating glycoprotein that is best known as a protease inhibitor. It has been used to treat emphysema patients with A1AT deficiency for decades. We and others have demonstrated its role in reducing acute lung injury by inhibiting inflammation, cell death, coagulation, and neutrophil elastase activation. Recently, A1AT has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by inhibiting transmembrane serine protease 2 (TMPRSS2), a protease involved in the entry of SARS-CoV-2 into host cells. This dual role of both antiviral infection and anti-inflammation makes A1AT a unique and excellent candidate for COVID-19 treatment. Three clinical trials of A1AT for COVID-19 treatment have recently been approved in several countries. It is important to determine whether A1AT can prevent the progress from moderate to severe lung injury and eventually to be used to treat COVID-19 patients with acute respiratory distress syndrome.

| S-EPMC7759674 | biostudies-literature

Motivating Protective Behavior against COVID-19: Fear Versus Hope.

Project description:ObjectivesBased on protection motivation theory, we investigate how indicators of threat perception (perceived severity, perceived vulnerability, and fear arousal) and coping appraisal (hope) are associated with older people's motivation to engage in protective behavior after the outbreak of COVID-19.MethodsWe use multivariate regression analyses with a sample of 40,282 individuals from 26 countries participating in the SHARE Corona Survey.ResultsWe find that 15% of all respondents stayed home completely-mainly the oldest and vulnerable people with prior health risk conditions. On average, older Europeans responded strongly to the recommended protective behavior measures (6 out of 7 measures adopted). Among the threat perception indicators, fear arousal is the main motivator for protective behavior, whereas the coping appraisal indicator hope shows an equally strong association.DiscussionGiven the negative health effects of fear, our findings may help evaluate and revise governmental policy responses and communication strategies.

| S-EPMC9207583 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data