Authors

M Radwanska¹; V Bockstal¹; J Cnops¹; S Moon¹; HT Nguyen¹; I Janssens¹; HT Pham¹; B Choi¹; V Deleeuw¹; FE Obishakin¹; C De Trez¹; S Magez¹;  ¹ Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology, Ghent University Global Campus, South Korea

Discussion

Salivarian trypanosomes are extracellular protozoan parasites causing infections in a wide range of mammalian hosts. The success of these parasites is attributed to their capacity to disable the immune system, resulting in a long-lasting infection, favoring parasite transmission. We demonstrate that mechanisms driving modulation of the innate and the adaptive immune responses take place in the bone marrow and the secondary lymphoid organs. As such, in the spleen mature IgM+CD1d+ Marginal Zone and IgMIntIgD+ Follicular B cells are rapidly depleted due to apoptosis and terminal differentiation into CD138+ Plasma cells. At the same time progressing ablation of the bone marrow immature CD93+ and Vpreb3+Ly6d+IghM+ transitional spleen B cells leads to the depletion of peripheral mature B cells. As a consequence, reduced number of new B cells can be generated, preventing the host from responding to newly emerging antigenic variants or remembering already encountered trypanosomes. In this context, the gradual infection-induced decrease in memory B cells was also demonstrated in the spleen. Strikingly, this B cell depletion coincided with large expansion the neutrophil population carrying cytotoxic load of metalloproteinases MMP-8 and MMP-9. The subsequent degranulation of these enzymes caused remodeling of the extracellular matrix (ECM), leading to severe damage of the spleen architecture, in the absence of a sufficient TIMP inhibitory activity. The scRNA-seq transcriptomic profiling indicated that expanded neutrophil population contained proliferating precursors, two immature subpopulations, and inflammation reprogrammed mature neutrophils. While usually neutrophils are associated with rapid and efficient pathogen removal, this seems not to be the case in trypanosome infections. Curiously, neutrophil depletion coincided with prolonged host survival, reduced organ damage, increased Plasma cell numbers, and improved systemic parasite control. Hence, the neutrophil cytotoxic signature genes constitute indicators of trypanosomiasis associated inflammation and pathology, seen also in T. b. rhodesiense sleeping patients.