# RAAS antagonists dampen the SARS-CoV-2 infection in ex-vivo cultured human precision-cut lung slices

## TL;DR

This study shows that drugs targeting the RAAS system can reduce SARS-CoV-2 infection and inflammation in human lung tissue.

## Contribution

The novel finding is that RAAS antagonists like enalapril and losartan reduce SARS-CoV-2 infection in human precision-cut lung slices.

## Key findings

- Both enalapril and losartan reduced SARS-CoV-2 replication in lung slices.
- Losartan was more effective at reducing inflammation markers like IL1B and CCL2.
- Enalapril decreased viral entry factors ACE2 and TMPRSS2 in infected tissue.

## Abstract

While the renin-angiotensin-aldosterone system (RAAS) is critically involved in pathomechanisms related to SARS-CoV-2 infection, the role of ongoing therapy with angiotensin-converting enzyme 1 inhibitors (ACEi) or Angiotensin-II type 1 receptor (AT1R) blockers (ARB) is much less clear. We evaluated the effects of the ACEi enalapril (ENA) and the ARB losartan (LOS) on SARS-CoV-2 infection in human ex vivo-cultured, precision-cut lung slices (PCLS) obtained from normal human lung tissue.

PCLS were pre-treated for 5d with vehicle, LOS or ENA (300 µM), followed by mock infection or infection with SARS-CoV-2 and incubation with vehicle, LOS or ENA for 1d or 2d. Thereafter, PCLS were harvested for analysis of viral replication, inflammatory responses, endoplasmic reticulum (ER) stress and apoptosis pathways.

Both LOS and ENA significantly reduced viral replication in PCLS, with ENA being more potent. LOS was more efficient than ENA in reducing the expression of IL1B, CCL2, CXCL2 and TNFA, but not of IL6, whereas ENA preferentially caused a reduction of IL6 and CCL2 in SARS-CoV-2-infected PCLS. Further, ENA, but not LOS, significantly decreased the expression of viral entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), in infected PCLS. Importantly, LOS or ENA did not exert cytotoxic effects.

RAAS-antagonizing drugs do not seem to exert detrimental effects during SARS-CoV-2 infection. In opposite, in an ex-vivo model of human PCLS, such treatment was found to dampen SARS-CoV-2 infection and consecutive inflammation.

The online version contains supplementary material available at 10.1186/s12931-025-03463-8.