Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis
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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.
Article activity feed
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SciScore for 10.1101/2020.08.14.248880: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Maintenance and generation of isogenic cell lines: Vero-CCL81, parental 293T, and isogenic 293T cells were cultured in DMEM with 10% heat inactivated FBS at 37ºC in the presence of 5% CO2. Vero-CCL81suggested: None293Tsuggested: NoneThe virus-serum mixture was then used to inoculate Vero E6 cells for one hour at 37ºC and 5% CO2. Vero E6suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. …
SciScore for 10.1101/2020.08.14.248880: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Maintenance and generation of isogenic cell lines: Vero-CCL81, parental 293T, and isogenic 293T cells were cultured in DMEM with 10% heat inactivated FBS at 37ºC in the presence of 5% CO2. Vero-CCL81suggested: None293Tsuggested: NoneThe virus-serum mixture was then used to inoculate Vero E6 cells for one hour at 37ºC and 5% CO2. Vero E6suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.08.14.248880: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Seronegative or seropositive samples were first identified based on IgG antibodies against Spike (Supplemental Fig. 1). Spike (Supplemental Fig. 1suggested: NoneExperimental Models: Cell Lines Sentences Resources The virus-serum mixture was then used to inoculate Vero E6 cells for one hour at 37ºC and 5% CO2. …SciScore for 10.1101/2020.08.14.248880: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Seronegative or seropositive samples were first identified based on IgG antibodies against Spike (Supplemental Fig. 1). Spike (Supplemental Fig. 1suggested: NoneExperimental Models: Cell Lines Sentences Resources The virus-serum mixture was then used to inoculate Vero E6 cells for one hour at 37ºC and 5% CO2. Vero E6suggested: NoneFor this experiment, sera samples were incubated with trypsin treated CoV2pp for 30mins prior to addition to Vero-CCL81 cells. Vero-CCL81suggested: NoneTrypsin treated CoV2pp (left panel) and standard VSV-Gpp (right) were diluted in serum free media, then used to infect VeroCCL81 cells in the presence of the indicated concentrations of albumin, AAT, or A2M. VeroCCL81suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
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