Trypanosome infections in cattle usually result in a chronic disease, characterized by anaemia, leukocytopaenia, immunosuppression and cachexia.

The parasites live in the bloodstream and evade immunological control by continuously varying their surface glycoprotein coat. Antibody to the surface-exposed epitopes of the variable surface glycoprotein coat (VSG) mediates the removal of a particular variant, but new variants expressing antigenically different VSGs appear throughout the infection. In cattle, following tsetse-fly transmitted infections, a fluctuating parasitaemia is observed, with-several variants expressed at any one time. Some breeds of cattle such as the N'Dama (Bos taurus) have evolved the ability to control both parasitaemia and anaemia. The control of these two traits does not appear to be linked. Trypanotolerant cattle remain more productive in trypanosomiasis-endemic areas than B. indicus breeds (such as the Boran), but can succumb to the disease when exposed to very high challenge or stress. ILRAD's immunopathology program aims to elucidate the mechanisms of trypano-tolerance and to identify trypanosome antigens which cause either protective or pathological responses in infected cattle. These antigens will be used in the design of novel vaccines which elicit protective anti-parasite immune responses or to block pathogenic responses. Results from studies on immune responses following T. congolense infections have shown that N'Dama cattle produce higher levels of IgG1 antibodies to invariant antigens (specifically, a trypanosome cysteine protease and a heat shock protein) and variant antigens; they have earlier and higher T-cell proliferative responses and their monocytes secrete higher levels of costimulatory cytokines (IL1/IL6) early in infection compared to trypanosusceptible cattle. A population of IgM antibodies which bind to non-trypanosome antigens has been identified in Borans but not in N'Damas. This population of antibodies also binds to trypanosome VSG, suggesting that they are polyspecific in origin. Studies are currently under way into differential epitope recognition and antibody avidity between the two breeds. There appear to be no differences between breeds in the titre or isotype of antibody specific for the surface-exposed epitopes of VSG. Both N'Dama and Boran cattle experience a profound macrophage-mediated immunosuppression in the lymph nodes early in infection. The antigen which induces this suppressor activity has been purified and is being characterized. Also a massive increase in the numbers of CD5+ B cells and in serum IgM levels has been described in all infected cattle. It has been suggested that the CD5+ B-cell response is the result of a T-independent response to VSG. The primary pathological feature of bovine trypanosomiasis is anaemia. The drop in red cells is due to the removal of both mature and immature erythrocytes by cells of the mononuclear phagocytic system (MPS) in the spleen and bone marrow. Results from in vivo and in vitro experiments suggest that erythrophagocytosis is higher in Borans than N'Damas. Data have also been obtained which indicate that in addition to the massive removal of erythrocytes by the MPS, there is insufficient red blood ceil replacement into the circulation. Analysis of erythroid progenitor colonies in bone marrow from trypanosusceptible cattle has shown that there is a suppression of both early (BFU-E) and late (CFU-E) progenitor cells early in infection. As the infection progresses the CFU-E progenitors recover, but the numbers of BFU-E's remain depressed. In summary, we have accumulated a database in which differences in the pathological consequences of trypanosome infection have been quantified in trypanotolerant and

trypanosusceptible cattle. Other factors which affect the outcome of disease are being addressed, such as the role of specific cytokines or the direct pathogenic effects on host molecules, cells or processes, of certain trypanosome antigens. Can we use the data we have to develop models to test the effect of altering variables such as aberrant cytokine production or the failure to develop T-dependent antibody responses? Can we test how these different immunological and haematological processes interact to affect the outcome of disease? Is it possible to model the interactions between innate host factors versus specific immune responses in control of parasite growth and the role of the immune and erythroid responses in the control of pathogenesis?