Altered granulopoiesis links influenza infection with acute plaque destabilization

• Applicant: Professor Dr. Oliver Söhnlein
• Subject Area: Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549860539

Atherosclerosis is the pathophysiology underlying myocardial infarction and stroke and can hence be held responsible for the majority of deaths worldwide. In previous work we have identified the crucial importance of neutrophils, the most abundant white blood cell in humans, during early and advanced stages of hyperlipidemia-triggered atherosclerosis. However, there is striking clinical evidence of the importance of acute infection for acceleration of atherosclerotic complications. In preparatory experiments for this project we witnessed a clear-cut acceleration of atherosclerosis in mice infected with Influenza A virus (IAV, H1N1). The infection was associated with rewiring of the bone marrow inducing production and release of immature neutrophils. Thus, we will here aim at establishing altered granulopoiesis as the culprit in influenza-accelerated atherosclerosis. Specifically, we will (I) investigate the dynamics of neutrophil production and arterial infiltration upon IAV infection and subsequently (II) characterization of neutrophil phenotypes in influenza infection using scRNAseq, proteomics, spectral flow cytometry and functional assays. Based on these analyses we will (III) dissect the contribution of neutrophil phenotypes to accelerated atherosclerosis and (IV) make use of patient samples to test changes in neutrophil phenotype and function in cardiovascular risk patients with documented influenza infection. Finally, we will use a series of preclinical intervention approaches to interfere with neutrophil-driven atheroprogession in IAV infected mice. Taken together, data generated within this proposal will address the important connection between an acute infection and atheroprogression and will generate a novel mechanistic understanding by focusing on altered granulopoiesis.

• DFG Programme: Research Grants