Alpha-1-Antitrypsin as an immune modulator upon SARS-CoV-2 infection
MELCHER L. 1, JERON A. 1,2, HIRSCH T. 1, BRUDER D. 1,2
1 Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany, Braunschweig, Germany; 2 Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University, Magdeburg, Germany , Magdeburg, Germany
COVID-19, caused by SARS-CoV-2, presents unprecedented challenges globally. It exhibits a wide range of clinical manifestations, from asymptomatic to fatal cases. Microvascular damage resulting from a hyperactive cytokine response, particularly associated with endothelial damage, is believed to be a consequence of COVID-19 infection. Targeting cytokines through anti-inflammatory therapies appears significant in treating COVID-19, but it remains unclear which specific inflammatory profiles correlate with symptom severity and impact the microvascular endothelium.
Alpha-1-antitrypsin (A1AT), a naturally occurring protein, is increased during inflammation as an essential acute-phase protein. Recent studies have shown that A1AT possesses potent immunomodulatory and immunosuppressive effects beyond its protease inhibitor role. A1AT specifically inhibits two proteases, TMPRSS2 and ADAM17, crucial for COVID-19 pathogenesis, and reduces levels of pro-inflammatory cytokines such as IL-1β, IL-8, and TNF-α. However, the therapeutic potential of targeting specific pro- and anti-inflammatory mediators to improve the clinical course of COVID-19, including reducing endothelial activation or damage, remains uncertain.
This study aims to investigate the immune-modulatory and immune-suppressive functions of A1AT in SARS-CoV-2 infections. Initially, we characterized the impact of A1AT on SARS-CoV-2 replication in human lung epithelial cells (Calu3) and its effect on the early immune response of these cells. Subsequently, we assessed the effect of A1AT treatment on COVID-19 pathogenesis in K18-hACE2 mice.
Preliminary data from human lung epithelial cells demonstrated that A1AT treatment, both during and after infection, reduced the number of infected cells and viral load. These findings align with previous studies on Vero E6 and CaCo2 cells (Wettstein et al., 2021). Further investigations will focus on transcriptomic changes, cytokine expression, and the potential of A1AT treatment to protect SARS-CoV-2-infected K18-hACE2 mice from severe COVID-19 pathogenesis.