Patrick Guirnalda, Magdalena Radwanska, Stefan Magez, Radhika Goenka, Guy Caljon, Janice C. Telfer, Viki Bockstal, Samuel J. Black, Deborah Frenkel, Cellular and Molecular Immunology, and Department of Bio-engineering Sciences
African trypanosomes of the Trypanosoma brucei species are extracellular protozoan parasites that cause the deadly disease African trypanosomiasis in humans and contribute to the animal counterpart, Nagana. Trypanosome clearance from the bloodstream is mediated by antibodies specific for their Variant Surface Glycoprotein (VSG) coat antigens. However, T. brucei infection induces polyclonal B cell activation, B cell clonal exhaustion, sustained depletion of mature splenic Marginal Zone B (MZB) and Follicular B (FoB) cells, and destruction of the B-cell memory compartment. To determine how trypanosome infection compromises the humoral immune defense system we used a C57BL/6 T. brucei AnTat 1.1 mouse model and multicolor flow cytometry to document B cell development and maturation during infection. Our results show a more than 95% reduction in B cell precursor numbers from the CLP, pre-pro-B, pro-B, pre-B and immature B cell stages in the bone marrow. In the spleen, T. brucei induces extramedullary B lymphopoiesis as evidenced by significant increases in HSC-LMPP, CLP, pre-pro-B, pro-B and pre-B cell populations. However, final B cell maturation is abrogated by infection-induced apoptosis of transitional B cells of both the T1 and T2 populations which is not uniquely dependent on TNF-, Fas-, or prostaglandin-dependent death pathways. Results obtained from ex vivo co-cultures of living bloodstream form trypanosomes and splenocytes demonstrate that trypanosome surface coat-dependent contact with T1/2 B cells triggers their deletion. We conclude that infection-induced and possibly parasite-contact dependent deletion of transitional B cells prevents replenishment of mature B cell compartments during infection thus contributing to a loss of the host's capacity to sustain antibody responses against recurring parasitemic waves., Author Summary African trypanosomiasis caused by Trypanosoma brucei species is fatal in both humans and animals and cannot be combated by vaccination because of extensive parasite antigenic variation. Effective trypanosome control and clearance from the bloodstream involves the action of antibodies specific for the parasite's highly diverse variable surface glycoprotein antigens. However, experimental infections in mice have shown that trypanosomiasis elicits a rapid process of B cell exhaustion and loss of protective antibody responses. Indeed, both marginal zone B cells, the first line of defense against blood-borne pathogens like T. brucei parasites, and follicular B cells, which are the major source for developing high-affinity antibody-producing plasma cells and memory B cells, become depleted during infection. In addition, existing B-cell memory, both against parasite antigens and non related pathogens, is destroyed early on in infection. Here, we demonstrate that during infection, B cell development is decreased in the bone marrow and early B cell development is taken over by the spleen. However, full maturation of developing B cells is abrogated by the occurrence of transitional B cell apoptosis. This impairs the replenishment of the mature marginal zone and follicular B cell pools and prevents the buildup of protective immunity against successive parasitemic waves.