The protective function of Interleukin-3 in secondary viral pneumonia during the immunosuppressive phase of sepsis

• Applicant: Professor Dr. Georg Weber
• Subject Area: General and Visceral Surgery ; Immunology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444596733

Sepsis is a life-threatening clinical syndrome related to the host response to infection. It can be divided into a phase of excessive inflammation followed by a phase of immunosuppression. The host response to infection is therefore not only an immediate and local process but a complex time- and space-compartmentalized event involving various cell types. The initial release of “inflammatory” cytokines induces new cytokine production and their release, causing cell and organ damage, and finally death. During the following immunosuppressive phase, patients are more sensitive to nosocomial infections and viral reactivation, which contributes to organs failure and finally, to death.Recently, we identified Interleukin-3 (IL-3) as a key modulator during acute inflammation in sepsis (Weber et al., Science, 2015). However, IL-3’s role in the following immunosuppressive phase during sepsis, in which secondary viral pneumonia occur, remains unclear. We hypothesise that IL-3 activates CD123+ lung epithelial cells resulting in the CXCL12 mediated translocation of type 1 interferon producing circulating mature plasmacytoid dendritic cells (pDCs) into the lung parenchyma, thus protecting against secondary viral pneumonia during the immunosuppressive phase in sepsis. Our hypothesis is based on several unpublished data: in a model of secondary viral pneumonia during septic immunosuppression, and as compared to controls, IL-3–/– mice are (i) more susceptible to secondary viral pneumonia; (ii) have reduced pDCs in the spleen and the lungs; (iii) have reduced type 1 interferon levels in the lungs; (iv) have increased viral load in the lungs; (v) do not show an increase of CXCL12, a chemokine that attracts leukocytes; and (vi) patients with reduced IL-3 serum levels have an increased risk for the development of secondary viral pneumonia.We will test the hypothesis using gene-knockout animal models, sophisticated surgical techniques, and classical molecular and cell biology tools. The project is important because it is based on a strong phenotype and has clear translational potential: IL-3 may be considered as a therapeutic target for the treatment of viral pneumonia, not only in the context of immunosuppression and sepsis. The project is innovative because it explores the biology of IL-3 during inflammatory disease with the potential of exploring new therapeutic strategies for sepsis and viral infections.

• DFG Programme: Research Grants