Interaction of Signaling Lymphocytic Activation Molecule Family 1 (SLAMF1) receptor with Trypanosoma cruzi is strain-dependent and affects NADPH oxidase expression and activity

The receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethalTrypanosoma cruziY strain. To elucidate whether genetic diversity of the parasite was related with disease susceptibility, we further analyzed the role of SLAMF1 using 6 differentTrypanosoma cruzistrains including Y. The interaction of SLAMF1 receptor withT.cruziwas evidenced by fluorescence microscopy, flow cytometry and quantitative PCR. All the strains, except VFRA, showed a decrease in parasite load in infected macrophages inSlamf1(-/-)compared to BALB/c. In macrophages gene expression NADPH oxidase (NOX2), and reactive oxygen species (ROS) production increased inSlamf1(-/-)compared to BALB/c in 5 out of 6 strains. However,Slamf1(-/-)macrophages infected with VFRA strain exhibited a divergent behavior, with higher parasite load, lower NOX2 expression and ROS production compared to BALB/c. Parasitological and immunological studiesin vivowith Y strain showed that in the absence of SLAMF1 the immune response protected mice from the otherwise lethal Y infection favoring a proinflammatory response likely involving CD4, CD8, dendritic cells and classically activated macrophages. In the case of VFRA, no major changes were observed in the absence of SLAMF1. Thus, the results suggest that theT.cruziaffects SLAMF1-dependent ROS production, controlling parasite replication in macrophages and affecting survival in mice in a strain-dependent manner. Further studies will focus in the identification of parasite molecules involved in SLAMF1 interaction to explain the immunopathogenesis of the disease. Author summary Chagas disease, caused byTrypanosoma cruzi, is characterized by an acute phase, with low mortality, and after many years without any sign of disease, patients develop a symptomatic chronic phase, characterized by cardiomyopathy and/or digestive mega syndromes. These differences have been attributed to the high genetic variability of this parasite. We have shown that the receptor Signaling Lymphocyte-Activation Molecule Family 1 (SLAMF1) controls susceptibility to Infection by the lethalT.cruziY strain. Here we studied in detail the immunopathogenic role of SLAMF1 using 6 genetically diverse strains ofT.cruziusingin vitroandin vivoapproaches. Our results indicate an important role of SLAMF1 inT.cruziinfection which is parasite strain-dependent. We found that parasites interact with SLAMF1 in macrophages affecting NADPH oxidase (NOX2) expression and reactive oxygen species (ROS) production 5 out of 6 strains tested. Y and VFRA strains showed a divergent behaviorin vitroand the role of SLAMF1 in thein vivoinfection was also strikingly different. The Y strain caused 70% mortality in BALB/c mice but not inSlamf1(-/-)mice. The proinflammatory response was stronger in the last, suggesting that SLAMF1 was repressing protective immune responses of mice infected with the Y strain. In contrast, for VFRA, SLAMF1 deficiency resulted in 100% survival of BALB/c mice, without major changes in the immune response in the absence of SLAMF1. Thus, the results indicate that SLAMF1 receptor interacts withT.cruzi, affecting parasite replication and ROS production in macrophages as well as the adaptive immune response in mice in a parasite strain-dependent manner. Future studies will focus in understanding the immunopathogenic role of SLAMF1 duringT.cruziinfection.