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-
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