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Published on: April 5, 2017
Leveraging human precision cut lung slices for the study of human parainfluenza virus 3 infection
Olga Danov1, Philippe Vollmer Barbosa1,2, Helena Obernolte1
1Fraunhofer Institute for Toxicology and Experimental Medicine, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Member of Fraunhofer International Consortium for Anti-Infective Research (iCAIR), Nicolai-Fuchs-Str. 1, Hannover, 30625, Germany.
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.
Insights
Human parainfluenza virus 3 (hPIV-3) causes severe respiratory illness. A new lung tissue model shows HN-inhibitors reduce viral load and inflammation, aiding antiviral drug development.
Area of Science:
- Virology
- Immunology
- Respiratory Medicine
Background:
- Human parainfluenza virus 3 (hPIV-3) is a significant cause of severe lower respiratory infections in vulnerable populations.
- Current treatment options, including vaccines and antivirals, are lacking for hPIV-3.
- Targeting the viral haemagglutinin-neuraminidase (HN) glycoprotein for viral entry inhibition shows therapeutic promise.
Purpose of the Study:
- To establish and validate a human lung tissue model for studying early hPIV-3 infection.
- To investigate the antiviral and inflammatory responses in human lung tissue following hPIV-3 infection.
- To assess the efficacy of HN-inhibitors in a relevant human tissue model.
Main Methods:
- Development of a human precision-cut lung slice (PCLS) model for hPIV-3 infection.
- Analysis of viral load, cellular infection patterns, and host inflammatory marker expression (interferons, chemokines, cytokines).
- Evaluation of prophylactic treatment with two HN-inhibitors in the PCLS model.
Main Results:
- hPIV-3 specifically infected small airway epithelial cells in PCLS.
- Infection induced a distinct antiviral response with type I, II, and III interferons, IP-10, ITAC, IL-6, and TNF-α, but limited IL-8.
- Prophylactic HN-inhibitor treatment significantly reduced hPIV-3 viral load and inflammation in PCLS.
Conclusions:
- The PCLS model effectively replicates early hPIV-3 infection and host responses in human lung tissue.
- HN-inhibitors demonstrate significant antiviral activity and reduction of inflammation in this human tissue model.
- The PCLS model is highly suitable for pharmacological assessment of novel hPIV-3 antiviral drugs.
