HAP-Chip: Dissecting the Pathomechanisms of Hospital-Acquired Pneumonia in an Immunocompetent Lung-on-Chip Model

• Applicant: Dr. Raquel Alonso-Roman
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576371913

Hospital-acquired pneumonia (HAP) is the most common nosocomial infection and represents a lethal complication for critically ill patients. HAP is often caused by opportunistic bacteria that cause disease only when the host defenses are compromised, for example, due to immunosuppression or preexisting lung injury. A major predisposing factor for HAP is mechanical ventilation, which results in ventilator-associated pneumonia (VAP). Mechanical ventilation disrupts epithelial barrier integrity and alters the alveolar environment (e.g., through acidification), leading to conditions favorable for bacterial infection. In addition, the immune response during HAP plays a critical dual role: robust responses are necessary to clear and control bacterial growth, but excessive inflammation can increase damage to the lungs. Understanding how individual predisposing factors contribute to disease progression is essential to develop therapeutic strategies that enhance host defenses and can reduce the high mortality of HAP and VAP. This project aims to dissect host-pathogen mechanisms during HAP, with and without the context of mechanical ventilation. To achieve this, I first aim to establish an immunocompetent lung-on-chip model, using primary alveolar epithelial and endothelial cells, alveolar macrophages, and circulating neutrophils. This model combines physiological relevance with precise control over host parameters, such as cell types and environmental conditions. Second, by using the lung-on-chip together with other advanced in vitro models, I aim to understand how disruptors of alveolar homeostasis caused by mechanical ventilation affect the onset and progression of VAP. Specifically, I will dissect the individual roles of the disruption of the epithelial barrier integrity and acidification of the alveolar environment on infections caused by Pseudomonas aeruginosa and Klebsiella pneumoniae. Finally, I aim at investigating the dual role of neutrophils and alveolar macrophages during the onset and development of HAP. For this, I will infect lung-on-chip models built without alveolar macrophages, neutrophils, or both types of immune cells. By comparing the disease progression and tissue damage across different conditions and timepoints, I aim to identify pathways or factors that can be immunomodulated in order to reduce inflammation-driven tissue damage. Collectively, this project will establish and employ advanced in vitro models to obtain in-depth mechanistic insights into the development and progression of HAP and VAP, and open new avenues that can improve the outcomes of patients with severe nosocomial infections.

• DFG Programme: Position