Therapeutic Application of Alpha-1 Antitrypsin in COVID-19.
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ABSTRACT:
SUBMITTER: Ritzmann F
PROVIDER: S-EPMC8650782 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Therapeutic Application of Alpha-1 Antitrypsin in COVID-19.
Ritzmann Felix F Chitirala Praneeth P Krüger Nadine N Hoffmann Markus M Zuo Wei W Lammert Frank F Smola Sigrun S Tov Naveh N Alagem Noga N Lepper Philipp M PM Pöhlmann Stefan S Beisswenger Christoph C Herr Christian C Bals Robert R
American journal of respiratory and critical care medicine 20210701 2
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Project description: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.
| S-EPMC7461031 | biostudies-literature
Project description:Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.
| S-EPMC8910375 | biostudies-literature
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
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
Project description:Alpha-1antitrypsin deficiency (AATD) results from the intracellular polymerization and retention of mutant alpha-1antitrypsin (AAT) within the endoplasmic reticulum of hepatocytes. This causes cirrhosis whilst the deficiency of circulating AAT predisposes to early onset emphysema. This is an exciting time for researchers in the field with the development of novel therapies based on understanding the pathobiology of disease. I review here augmentation therapy to prevent the progression of lung disease and a range of approaches to treat the liver disease associated with the accumulation of mutant AAT: modifying proteostasis networks that are activated by Z AAT polymers, stimulating autophagy, small interfering RNA and small molecules to block intracellular polymerization, and stem cell technology to correct the genetic defect that underlies AATD.
| S-EPMC6361470 | biostudies-literature
Project description:BackgroundPatients with alpha-1 antitrypsin deficiency (AATD) exhibit dysregulated inflammatory responses and a predilection for autoimmunity. While the adverse event (AE) profiles of COVID-19 vaccines in several chronic inflammatory conditions are now available, safety and tolerability data for patients with severe AATD have yet to be described. The feasibility of coadministering vaccines against COVID-19 and influenza in this population is similarly unclear.MethodsWe conducted a prospective study of 170 patients with Pi*ZZ genotype AATD receiving their initial vaccination series with ChAdOx1 nCoV-19 (AstraZeneca). Patients were monitored clinically for AEs over the week that followed their first and second doses. In parallel, we conducted the same assessments in patients with Pi*MM genotype chronic obstructive pulmonary disease (COPD) (n=160) and Pi*MM individuals without lung disease (n=150). The Pi*ZZ cohort was subsequently followed through 2 consecutive mRNA-based booster vaccines (monovalent and bivalent BNT162b2, Pfizer/BioNTech). To assess the safety of combined vaccination against COVID-19 and influenza, the quadrivalent influenza vaccine was administered to participants attending for their second COVID-19 booster vaccination, either on the same day or following a 1-week interval.ResultsPi*ZZ AATD participants did not display increased AEs compared to Pi*MM COPD or Pi*MM non-lung disease controls. Although unexpected and serious vaccine-associated AEs did occur, the majority of AEs experienced across the 3 groups were mild and self-limiting. The AATD demographic at highest risk for AEs (especially systemic and prolonged AEs) was young females. No increase in AE risk was observed in patients with established emphysema, sonographic evidence of liver disease, or in those receiving intravenous augmentation therapy. AE incidence declined sharply following the initial vaccine series. Same-day coadministration of the COVID-19 mRNA bivalent booster vaccine and the annual influenza vaccine did not result in increased AEs compared to sequential vaccines 1 week apart.ConclusionsDespite their pro-inflammatory state, patients with severe AATD are not at increased risk of AEs or serious AEs compared to patients with nonhereditary COPD and patients without lung disease. Same-day coadministration of COVID-19 booster vaccines with the annual influenza vaccine is feasible, safe, and well-tolerated in this population.
| S-EPMC10913930 | biostudies-literature
Project description:IntroductionAlpha-1-antitrypsin (AAT) has been shown to inhibit SARS-CoV-2 cell entry and suggested as a therapeutic agent for COVID-19. Furthermore, epidemiological association of high prevalence of Alpha-1-antitrypsin deficiency (AATD) and regional severity of COVID-19-impact has been hypothesized. In our study setting, the estimated prevalence rates of mild (PI*MZ, PI*SS or PI*MS) and moderate-to-severe AATD (PI*ZZ or PI*SZ) are high, 9% and 0.2%, respectively. Our primary aim was to examine the prevalence rate of AATD among hospitalized COVID-19-patients.MethodsIn this prospective observational study, enrollment occurred from December 2020 to January 2021 in two COVID-19-units at Skåne University Hospital, Lund, Sweden. Case definition was a patient hospitalized due to COVID-19. Patients were screened for AATD with PI-typing and if results were inconclusive, PCR for the S- and Z-genes were performed. Patients were categorized as severe or moderate COVID-19 and 30-day-mortality data were collected. The primary outcome was prevalence rate of AATD. The secondary outcome investigated association between presence of mild AATD and severe COVID-19.ResultsWe enrolled 61 patients with COVID-19. Two patients out of 61 (3%) had mild AATD (PI*MZ) and none had moderate-to-severe AATD. 30/61 (49%) had severe COVID-19. Both patients with mild AATD developed severe COVID-19. Yet, presence of AATD was not significantly associated with severe COVID-19 (p=0.24).ConclusionMild AATD (PI*MS or PI*MZ) was rare in a small cohort of hospitalized patients with COVID-19 in a study setting with a high background prevalence of AATD.
| S-EPMC9250346 | biostudies-literature
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
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
Project description:Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are "COVID-19 friendly", thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter.
| S-EPMC8570922 | biostudies-literature