Dataset Information

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

ABSTRACT:

Rationale

SARS-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.

Objectives

We 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.

Findings

Our 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.

Conclusions

AAT 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.

SUBMITTER: Stevens CS

PROVIDER: S-EPMC7430570 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

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

Stevens Christian S CS Oguntuyo Kasopefoluwa Y KY Oguntuyo Kasopefoluwa Y KY Kowdle Shreyas S Kowdle Shreyas S Brambilla Luca L Brambilla Luca L Haas Griffin G Gowlikar Aditya A Siddiquey Mohammed Na MN Schilke Robert M RM Woolard Matthew D MD Zhang Hongbo H Acklin Joshua A JA Ikegame Satoshi S Huang Chuan-Tien CT Lim Jean K JK Cross Robert W RW Geisbert Thomas W TW Ivanov Stanimir S SS Kamil Jeremy P JP Lee Benhur B

bioRxiv : the preprint server for biology 20230508

<h4>Rationale</h4>SARS-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.<h4>Objectives</h4>We aimed to investigate the role of naïve serum and alpha-1-antitrypsin (AAT) in inhibiting protease-mediated SARS-CoV-2 entry and explo ...[more]

PMID: 32817940

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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.

Project description:SERPINA1/AAT/α-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1E342K/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury. Both proteasome and macroautophagy/autophagy pathways are responsible for disposal of SERPINA1E342K/ATZ after it accumulates in the ER. However, the mechanisms by which SERPINA1E342K/ATZ is selectively degraded by autophagy remain unknown. Here, we showed that ER membrane-spanning ubiquitin ligase (E3) SYVN1/HRD1 enhances the degradation of SERPINA1E342K/ATZ through the autophagy-lysosome pathway. We found that SYVN1 promoted SERPINA1E342K/ATZ, especially Triton X 100-insoluble SERPINA1E342K/ATZ clearance. However, the effect of SYVN1 in SERPINA1E342K/ATZ clearance was impaired after autophagy inhibition, as well as in autophagy-related 5 (atg5) knockout cells. On the contrary, autophagy induction enhanced SYVN1-mediated SERPINA1E342K/ATZ degradation. Further study showed that SYVN1 mediated SERPINA1E342K/ATZ ubiquitination, which is required for autophagic degradation of SERPINA1E342K/ATZ by promoting the interaction between SERPINA1E342K/ATZ and SQSTM1/p62 for formation of the autophagy complex. Interestingly, SYVN1-mediated lysine 48 (K48)-linked polyubiquitin chains that conjugated onto SERPINA1E342K/ATZ might predominantly bind to the ubiquitin-associated (UBA) domain of SQSTM1 and couple the ubiquitinated SERPINA1E342K/ATZ to the lysosome for degradation. In addition, autophagy inhibition attenuated the suppressive effect of SYVN1 on SERPINA1E342K/ATZ cytotoxicity, and the autophagy inducer rapamycin enhanced the suppressive effect of SYVN1 on SERPINA1E342K/ATZ-induced cell apoptosis. Therefore, this study proved that SYVN1 enhances SERPINA1E342K/ATZ degradation through SQSTM1-dependent autophagy and attenuates SERPINA1E342K/ATZ cytotoxicity.

Dataset Information

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

Rationale

Objectives

Findings

Conclusions

Publications

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

Similar Datasets

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