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Trypanosoma brucei is the causative agent of both sleeping sickness in humans and the related veterinary disease, Nagana. Both diseases have a wide distribution across sub-Saharan Africa and affect some of the poorest areas of the world. T. brucei can be segregated into three morphologically identical sub-species based on host, geography and pathology. T. b. brucei is limited to domestic and wild animals throughout sub-Saharan Africa and is non-infective to humans due to trypanosome lytic factors found in human serum. T. b. gambiense and T. b. rhodesiense are human infective sub-species, named due to their relative geographic locations. T. b. gambiense is the dominant form of the disease, causing over 90% of reported cases. Study of T. b. gambiense is complicated in that there are two distinct groups. Group 1 is invariably resistant to lysis and by far the more prevalent group. Group 2 T. b. gambiense exhibit a variable resistance phenotype and are only found at a small number of Côte d’Ivoire disease foci. There are two trypanosome lytic factors in human serum (TLF-1 & 2), both containing the proteins Apolipoprotein L1 (ApoL1) and Haptogoblin-related protein (Hpr). It has been conclusively demonstrated that the lytic component of TLF is ApoL1, although Hpr is required for maximal lysis by facilitating uptake of TLF particles via the HpHbR cell surface receptor. This thesis has exposed several features of the human infectivity phenotype in both groups of T. b. gambiense, an area of research for which data has been lacking due to the difficulty of working with the organism. Fluorescence microscopy indicated that group 1 T. b. gambiense exhibit avoidance of TLF-1 particles by down-regulating HpHbR receptor expression and function. However, they are also able to resist the effects of recombinant ApoL1, suggesting an additional neutralisation or compensatory mechanism. Due to group 1 T. b. gambiense avoidance of TLF-1, TLF-2 is the more important lytic particle for this sub-species group and future research must take this into consideration. Unlike group 1, group 2 T. b. gambiense displays a variable human serum resistance phenotype that involves a neutralisation or compensatory mechanism for ApoL1, with no significant avoidance of lytic particles. Despite the high variability of the phenotype of group 2 T. b. gambiense, Quantitative Trait Analysis (QTL) using twenty-five F1 progeny from a T. b. brucei / group 2 T. b. gambiense cross indicated a strong heritable component to human serum resistance largely determined by a 30 gene locus on chromosome 8. Finally, a six multi-locus genotype population analysis of a Côte d’Ivoire T. b. gambiense focus was conducted, revealing little relationship between the two groups of T. b. gambiense in the field. The differences in the human serum resistance phenotypes and population genetics of both groups of T. b. gambiense revealed both prior and during this study make it appear likely that the two groups have evolved distinct human serum resistance strategies.

Rodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation.