COVID-19 infection in severe Alpha 1-antitrypsin deficiency: Looking for a rationale

Ferrarotti, Ilaria; Ottaviani, Stefania; Balderacchi, Alice Maria; Barzon, Valentina; Silvestri, Annalisa De; Piloni, Davide; Mariani, Francesca; Corsico, Angelo Guido

doi:10.1016/j.rmed.2021.106440

Cited by 32 publications

(17 citation statements)

References 10 publications

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“…The authors found a higher frequency of SARS-CoV-2 infection in the AATD cohort (3.8%) compared to the national data regarding infection, and patients with severe AATD had a relative risk of 8.8 (95% confidence interval (CI): 5.1–20.0; p < 0.0001) for symptomatic SARS-CoV-2 infection. Moreover, the relative risk (RR) was higher in patients with AATD and pre-existing lung diseases (RR 13.9; 95% CI: 8.0–33.6; p < 0.001) [ 30 ].…”

Section: Aatd and Covid-19: Geographical Overlap And Data From Clinical Registriesmentioning

confidence: 99%

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

Vianello

Guarnieri

Braccioni

et al. 2021

JCM

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The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19.

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Section: Aatd and Covid-19: Geographical Overlap And Data From Clinical Registriesmentioning

confidence: 99%

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

Vianello

Guarnieri

Braccioni

et al. 2021

JCM

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“…COVID-19 cases are increased in areas of Italy with an increased prevalence of AAT deficiency 11 . AAT deficient subjects were 8.8-fold more likely to have symptomatic COVID-19 than the general Italian population 12 . Shapira and colleagues 13 found a significant direct correlation between the frequency of the protease inhibitor (Pi)Z and PiS alleles with COVID-19 death rates in 67 countries.…”

Section: Introductionmentioning

confidence: 87%

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

Bai

Buckle

Vladar

et al. 2022

Sci Rep

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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.

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“…Indeed, several studies pointed to a tentative link between lower blood AAT levels and severe Covid-19, suggesting that AAT deficiency contributes to Covid-19 fatalities (Faria et al, 2021;Ferrarotti et al, 2021;Shapira et al, 2020;Shimi et al, 2021;Vianello & Braccioni, 2020). Indeed, bioengineered AAT, which is approved for treating lung inflammation in AAT deficient individuals, was proposed as potential therapeutic for Covid-19 (Marzouk et al, 2021;Yang et al, 2020;Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The reduced expression of SERPINA1 , coding for alpha‐1 antitrypsin (AAT), observed following chronic d ‐galactose treatment, also suggests higher SARS‐CoV‐2 infection load: AAT readily inhibits TMPRSS2 (Azouz et al, 2021; Wettstein et al, 2021), which is essential for priming SARS‐CoV‐2 for cell entry (Azouz et al, 2021; Hoffmann et al, 2020). Indeed, several studies pointed to a tentative link between lower blood AAT levels and severe Covid‐19, suggesting that AAT deficiency contributes to Covid‐19 fatalities (Faria et al, 2021; Ferrarotti et al, 2021; Shapira et al, 2020; Shimi et al, 2021; Vianello & Braccioni, 2020). Indeed, bioengineered AAT, which is approved for treating lung inflammation in AAT deficient individuals, was proposed as potential therapeutic for Covid‐19 (Marzouk et al, 2021; Yang et al, 2020; Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

Baristaite

Genevieve

2021

Drug Dev Res

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Several comorbidities including diabetes, immune deficiency, and chronic respiratory disorders increase the risk of severe Covid‐19 and fatalities among SARS‐CoV‐2 infected individuals. Severe Covid‐19 risk among diabetes patients may reflect reduced immune response to viral infections. SARS‐CoV‐2 initially infects respiratory tract epithelial cells by binding to the host cell membrane ACE2, followed by proteolytic priming for cell entry by the host cell membrane serine protease TMPRSS2. Additionally, the protease FURIN facilitates cell exit of mature SARS‐CoV‐2 virions. Alpha‐1 antitrypsin (AAT), the major plasma serine protease inhibitor, encoded by SERPINA1, is known to promote immune response to viral infections. AAT inhibits neutrophil elastase, a key inflammatory serine protease implicated in alveolar cell damage during respiratory infections, and AAT deficiency is associated with susceptibility to lung infections. AAT is implicated in Covid‐19 as it inhibits TMPRSS2, a protease essential for SARS‐CoV‐2 cell entry. Here we show that treatment of A549 human lung epithelial cells for 7 days with 25 mM d‐galactose, an inducer of diabetic‐like and oxidative stress cellular phenotypes, leads to increased mRNA levels of ACE2, TMPRSS2, and FURIN, along with reduced SERPINA1 mRNA. Together, the dysregulated transcription of these genes following d‐galactose treatment suggests that chronic diabetic‐like conditions may facilitate SARS‐CoV‐2 infection of lung epithelial cells. Our findings may in part explain the higher severe Covid‐19 risk in diabetes, and highlight the need to develop special treatment protocols for diabetic patients.

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COVID-19 infection in severe Alpha 1-antitrypsin deficiency: Looking for a rationale

Cited by 32 publications

References 10 publications

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

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

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

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