T. brucei Infection Reduces B Lymphopoiesis in Bone Marrow and Truncates Compensatory Splenic Lymphopoiesis through Transitional B-Cell Apoptosis

Abstract

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.

The Trypanosoma brucei gambiense Secretome Impairs Lipopolysaccharide-Induced Maturation, Cytokine Production, and Allostimulatory Capacity of Dendritic Cells

“…Recently, natural killer T cells and regulatory T cells have been demonstrated to influence the outcome of a trypanosome infection (41)(42)(43). Moreover, trypanosomes are also capable of reducing B lymphopoiesis and selectively destroying B-cell populations (44,45). The previous short description of immunological disorders induced by trypanosomes makes one believe that the trypanosome has developed a strategy of communication through paracrine mediators to dysregulate immune functions in a discrete manner, in addition to the powerful mechanism of VSG switching.…”

Infection-Induced Changes in Hematopoiesis

“…The BM is also a site of B cell development and many infections can profoundly impact this process (47, 69–74). Challenge with influenza or LCMV results in a transient decrease in pro, pre, and immature B cells in the BM, which is in part dependent on TNFα and lymphotoxin α (71, 72).…”

Inflammation rapidly reorganizes mouse bone marrow B cells and their environment in conjunction with early IgM responses

“…7,14,15 Using either adjuvant or infection models, it has also been observed that lymphopoiesis is rapidly repressed and B cells make an exodus to the periphery mediated by reduced availability of CXCL12. 16,17 This phenomenon is thought to make way for emergency granulopoiesis, a condition of elevated granulocyte maturation that occurs to replace innate immune cells, which may have been lost in the initial onslaught against a pathogen. 18,19 However, this model does not explain how bone marrow B cells are able to produce antibody responses despite apparent instability of the population and their environment.…”