Prothrombotic interplay between valvular macrophages, circulating monocytes and platelets as initiators and facilitators of bacterial infestation in infective endocarditis

• Applicant: Dr. Rainer Kaiser
• Subject Area: Cardiology, Angiology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535810218

As part of ancestral defense mechanisms, innate immune cells are equipped with a broad weaponry of cytotoxic molecules, adhesion receptors and phagocytosis mechanisms that enable swift eliminiation of invading pathogens. Circulating platelets, which have bactericidal capacity on their own and also affect leukocyte recruitment and activation, especially support myeloid cells in carrying out their deeds. Despite aiming at protecting the host organism through dampening invasive infection, the reciprocal hyperactivation of myeloid cells and platelets can lead to local tissue damage and global organ failure. This pathological state, termed thromboinflammation, describes a generalized trend towards systemic, unspecific immune cell activation associated with diffuse coagulopathy and converts the protective mechanisms of reciprocal activation into self-inflicted damage. Infective endocarditis (IE), the infection of the heart's inner skin and specifically its valves through highly virulent microbes such as Staphylococcus aureus, is a potentially lethal disease that is characterized by systemic activation of platelets, clotting factors and innate immune cells. Due to its unspecific symptoms, a prolonged time to diagnosis as well as both local and systemic complications, infective endocarditis is associated with a high mortality rate of up to 30% within one month. While previous work has mainly focused on the interaction of platelets with bacteria and the role of neutrophils in pathogen containment, it is unclear whether circulating monocytes and valve-resident macrophages also contribute to the initiation and progression of IE. In preliminary work, which is part of a translational immunophenotyping study encompassing IE patients, I have investigated circulating monocytes and valve-resident macrophages using modern profiling techniques such as single-cell RNA sequencing and mass spectrometry-based proteomics. Here, both circulating monocytes and valve-resident macrophages show upregulation of prothrombotic pathways as well as monocytic infiltration and concomitant reduction of valve-resident macrophages in resected valves derived from IE patients. Within the scope of this project, I want to use murine models of S. aureus-induced IE, transgenic mouse lines, functional in vitro methods as well as state-of-the-art multi-omics techniques in order to investigate how circulating monocytes and valve-resident macrophages and their interplay with platelets contribute to the initiation and progression of IE. The overarching aim of this study is to identify IE-specific immune cell signatures in monocytes and macrophages to enable mechanistic insight into their role in the pathophysiology of IE, but also to identify novel diagnostic and therapeutic targets for this potentially lethal disease.

• DFG Programme: Research Grants