Role of the C-type lectin receptor MINCLE in Strongyloides ratti recognition and anti-helminth immune responses

点击翻译按钮获取中文摘要

The mammalian immune system protects us against infections with a plethora of different pathogens that require a customized combination of immune effector cells to be efficiently controlled. C-type lectin receptors (CLR) represent an ancient family of pattern recognition receptors (PRR) and are involved in both, the recognition of pathogens and the initiation and shaping of appropriate immune responses. Helminth parasites still infect ca. 2 billion humans worldwide and have evolved sophisticated mechanisms to avoid their immune-driven elimination by active modulation of their host immune system.This proposal intends to investigate the role of the Macrophage-inducible CLR (MINCLE) during Strongyloides ratti infection (a model of human hookworm infection), focusing on helminth-induced immune modulation. It brings together the expertise of the Lepenies laboratory regarding CLR biochemistry and the Breloer laboratory regarding helminth immunology and helminth-induced immune modulation. In preliminary experiments, we recorded binding and activation of MINCLE by S. ratti lysate, thus indicating the presence of agonistic MINCLE ligands. Binding of S. ratti-derived ligands to MINCLE was biologically relevant since MINCLE-deficient mice displayed a decreased intestinal parasite burden accompanied by an increased production of type 2 associated cytokines during S. ratti infection. Thus, MINCLE engagement by S. ratti-derived products may be exploited to modulate the appropriate type 2 immune responses needed for efficient parasite expulsion. This hypothesis is further encouraged by the fact that mice lacking CARD9, an adaptor molecule that is involved in MINCLE-mediated signalling, phenocopied MINCLE-deficient mice. While immune modulating functions for MINCLE were shown by several groups during fungal and protist parasite infection, there is a gap of knowledge regarding the role of MINCLE during helminth infections.Within this proposal, we intend to identify helminth-derived MINCLE ligands on a molecular level, using a methodology already established in the Lepenies laboratory. Employing the S. ratti infection model established in the Breloer laboratory, we aim to identify the immune effectors that are modulated by MINLCE-mediated signalling. Analysing the stimulatory capacity and the activation status of APC that will be activated in the presence of helminth-derived MINCLE ligands in vitro, we intend to elucidate the underlying molecular mechanisms. In summary, we expect to unravel a novel pathway of helminth-mediated immune evasion via engagement of MINCLE.