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

Abstract

Strongyloides ratti is a parasitic nematode with tissue migrating and intestinal life stages. Recognition of pathogens and initiation of immune responses is promoted by interaction between pattern-recognition-receptors (PRRs) on immune cells and pathogen-associated-molecular-patterns (PAMPs) present on the parasite. Screening a crude S. ratti-derived protein lysate against a library of C-type lectin receptors (CLR), an ancient family of PRR, we found that Macrophage-inducible-C-type lectin receptor (MINCLE) binds immobilized S. ratti lysate and activates a MINCLE expressing reporter cell line. As this suggests presence of agonistic MINCLE-ligands in the S. ratti lysate, we analysed a putative function for MINCLE in vivo. Strikingly, MINCLE-deficient (KO) mice displayed reduced intestinal S. ratti parasite burden compared to their wildtype (WT) mice, suggesting an improved and not the expected impaired host defence in the absence of a stimulating PRR. To elucidate, which effector cell expressing MINCLE might be responsible for this protective immunity, we show that eosinophils and neutrophils represent the dominant MINCLE expressing cell population in vivo. Comparing their function in vitro, WT and MINCLE KO granulocytes inhibited motility of S. ratti third stage larvae (L3), indicating potential killing of L3. However, MINCLE-deficient eosinophils showed significantly increased capacity to impair S. ratti motility. These cells also produced more reactive oxygen species (ROS) compared to the WT. Therefore, indicating that, MINCLE-mediated signalling changes the function of eosinophils during S. ratti infection. Thus, expression of MINCLE on eosinophils protect S. ratti from immune response by host and as a result, contributing to high parasite adults in the intestine.