SARS-CoV-2 induced damage of the alveolar epithelium in the lung and its inhibition by α1-antitrypsin.

• Applicants: Professor Dr. Manfred Frick; Professor Dr. Jan Münch
• Subject Area: Anatomy and Physiology ; Virology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458685747

The health emergency caused by the recent coronavirus disease 2019 (COVID-19) pandemic highlights the need to identify effective treatments against the causative severe respiratory syndrome coronavirus 2 (SARS CoV-2). SARS-CoV-2 infection primarily targets the respiratory tract. Recent studies suggest that nasal surfaces might be the dominant initial site for SARS-CoV-2 respiratory tract infection. This is followed by aspiration of the viral inoculum into the distal lung and infection of alveolar type II pneumocytes (ATII cells). The most severe infections with SARS-CoV-2 result in acute respiratory distress syndrome (ARDS) caused by structural and/or functional damage of the alveolar air-blood barrier. About 25% of these patients will require mechanical ventilation, which is associated with high mortality (50 to 80%). This clinical phenotype is thought to arise as the virus progressively targets the epithelium of the distal lung, particularly ATII cells. The mechanisms, however, that cause virus-induced pathological changes in the alveolus and the alveolar epithelium are still poorly understood. Thus, it is a main aim of this proposal is to investigate the effect of SARS-CoV-2 infection on alveolar epithelial cell function and alveolar barrier integrity. The severity in COVID-19 induced ARDS is tightly correlated with alveolar SARS-CoV-2 viral load. Reducing infectious virus load in the alveolar compartment will therefore reduce COVID-19 ARDS severity. We recently identified the acute phase protein α1-antitrypsin (α1-AT) from bonchioalveolar lavages as specific inhibitor of SARS-CoV-2. Endogenous α1-AT is a broad-spectrum serine protease inhibitor (serpin) that is upregulated during SARS-CoV-2 infection. We found that α1-AT inhibits SARS-CoV-2 infection of human airway epithelia at physiological concentrations. Our findings showed that α1-AT may serve as natural inhibitor of SARS-CoV-2 infection, in particular during acute infection when α1-AT concentrations increase. Moreover, this potentially offers an opportunity for repurposing of already approved α1-AT-based drugs for COVID-19 therapy. In fact, several clinical trials have been initiated to evaluate the therapeutic efficacy of α1-AT in hospitalized COVID-19 patients. Thus, the second aim of our proposal is to investigate whether α1-AT reduces SARS-CoV-2 infection in alveolar epithelia, in particular ATII cells, and protects from alveolar barrier damage. To address these two aims we will use human primary isolated ATII cells and recently established in vitro models of the alveolar-capillary barrier and infect these with SARS-CoV-2 isolates obtained from different geographical regions. We will analyze the effects of SARS-CoV-2 infection on alveolar barrier integrity and function, and clarify whether α1-AT may suppress viral infection and damage.

• DFG Programme: Research Grants