Development of host directed therapies against viral pneumonia by targeting plasmacytoid dendritic cell trafficking.

• Applicant: Alan Bénard, Ph.D.
• Subject Area: Immunology ; Pneumology, Thoracic Surgery ; Virology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532458300

Pneumonia is a leading cause of hospitalizations in adults and children, with high medical costs. While bacterial pneumonia can be treated with broad-spectrum antibiotics, treatment for viral pneumonia targets a specific virus and its close relatives. The emergence of new zoonotic viruses with pandemic potential (e.g. SARS-CoV-2) draws attention to the limitations of current antiviral treatment and the urgent need for alternative therapeutic strategies. One of the strategies is the development of new therapies that strengthen the antiviral immune response. However, this requires a thorough mechanistic understanding of the pathophysiology of the disease. We recently showed that CXCL12 attracts antiviral plasmacytoid dendritic cells (pDCs) to the airways during viral pneumonia, resulting in better protection (1). Therefore, the identification of new targets that promote recruitment of pDCs to the lungs could enable the development of novel host-directed therapies against viral pneumonia. This is the focus of our current work. In this project we will investigate the role of CXCR4 and CXCR7, the receptors of CXCL12, during viral pneumonia. First, we examine the effect of AMD3100, a CXCR4 antagonist, on viral pneumonia (AIM 1). Furthermore, we will unravel the role of CXCR7 on the antiviral function of pDCs (AIM 2). This project is important and innovative for many reasons. First, it is based on a solid phenotype in vivo that clearly shows that i) AMD3100 appears to protect against viral pneumonia; ii) VUF11207, a chemical agonist of CXCR7, promotes migration of pDC to the lung; and iii) patients with viral pneumonia have reduced CXCR7 expression on the surface of pDCs compared to patients without viral pneumonia. Second, this project will highlight novel functions of CXCR7, a receptor whose functions are poorly understood. Third, it will make a significant contribution to translational research.

• DFG Programme: Research Grants