# Leveraging human precision cut lung slices for the study of human parainfluenza virus 3 infection

## TL;DR

This study uses human lung tissue slices to model hPIV-3 infection and test antiviral drugs, showing reduced viral load and inflammation with HN inhibitors.

## Contribution

The novel contribution is establishing a human precision-cut lung slice model to study hPIV-3 infection and evaluate antiviral treatments.

## Key findings

- Small airway epithelial cells show specific infection with hPIV-3 and produce interferons and chemokines.
- Prophylactic HN inhibitors significantly reduce viral load and inflammation in human lung tissue slices.
- Limited induction of severe cytokines like IL-8 suggests lower clinical severity in the model.

## Abstract

Human parainfluenza virus 3 is a highly abundant RNA virus that primarily affects young children, the elderly, and immunocompromised individuals, leading to severe lower respiratory infections and pneumonia. Despite an urgent need of treatment options for these high-risk patients, neither a vaccine nor specific antiviral are currently approved. Blocking viral entry by targeting the viral surface glycoprotein haemagglutinin-neuraminidase (HN) has shown promising results in vitro and, to some extent, in vivo. However, to further evaluate these antiviral approaches for potential human application, a detailed understanding of early hPIV-3 infection and drug treatment mechanisms in human lung tissue is needed. In this study, we established a model for early hPIV-3 infection in human precision-cut lung slices (PCLS). We demonstrate specific infection of small airway epithelial cells followed by a distinct antiviral and inflammatory response marked by expression and secretion of type I, II and III interferons, chemokines such as IP-10 and ITAC, and pro-inflammatory markers IL-6 and TNF-α, but only limited induction of cytokines associated with high clinical severity, such as IL-8. Prophylactic treatment with two viral entry HN-inhibitors significantly reduced hPIV-3 viral load and inflammatory response after infection in the human lung tissue slices, demonstrating the high usability of the PCLS infection model for pharmacological assessment of novel antiviral drugs.

The online version contains supplementary material available at 10.1186/s12931-025-03335-1.