Immunosurveillance of the blood stream by mast cells: Protection against circulating microorganisms, microbial toxins and animal venoms?

• Applicant: Professor Dr. Axel Roers
• Subject Area: Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557176285

We recently found that anaphylaxis to blood-borne allergen depends on a subset of MCs that is tightly associated with blood vessels and probes vessel content. Beneficial functions of this MC surveillance of the blood stream, however, remain unknown. Invasion of the blood by exogenous hazards poses a per-acute threat and accounts for vast numbers of severe disease and fatalities. We hypothesize that perivascular MCs detect and rapidly protect against three classes of circulating hazards: I) Septicemia, II) microbial exotoxins and III) animal venoms. Our novel mouse model, in which selectively the MCs lack expression of integrin ß1 (ITGB1) allows to test these hypotheses. In these mice, MCs show intact degranulation responses, but fail to interact with blood vessels. To assess MC-dependent protection against blood-borne bacteria, which we posit was not settled by models used in the past, we will intravenously inject bacterial PAMPs or bacteria. Antimicrobial MC functions likely don’t overlap with those of circulating neutrophils, monocytes or the complement system. As the key feature of MCs is the speed of their responses, we rather hypothesize, that MCs contribute fast alarm signals that sensitize intravascular cells or the complement system, increasing sensitivity and preparedness for pathogen encounter. We will quantify impact of intravascular injections of PAMPs or bacteria on leukocyte and platelet counts, cytokine levels, complement activation, coagulopathy, monocyte and neutrophil transcriptomes, bacterial clearance, as well as body temperature and survival. We will test single and repeated exposure. In addition to testing naïve mice, we will also address IgE-dependent protection in mice epicutaneously sensitized to bacteria. MC-mediated protection against circulating microbial toxins will be addressed by first testing whether toxins degranulate MCs in vitro and whether they are degraded by components of the MC secretome. We will then assess MC-mediated in vivo protection against intravenous toxin challenge. MC were shown to protect against snake venom in vivo. Circulating venom causes multi-organ damage with frequently fatal outcome. Whether perivascular MCs play a specialized role by detection and inactivation of circulating venom is unknown and will be addressed by intravenous venom exposure in naïve and sensitized mice. Readouts will include body temperature, coagulopathy, serum transaminases and LDH indicating cellular damage, and vascular leakage. Finally, we will investigate the structural nature of the MC-vessel association by electron microscopy and clarify functional interactions of MCs with cells of the vessel wall. Identification of hazards perivascular MCs have evolved to protect us from will greatly advance our still incomplete understanding of roles MCs play in the immune system. Elucidation of mechanisms by which MCs protect against these hazards holds great promise to instruct novel prophylactic or therapeutic strategies.

• DFG Programme: Research Grants