Differences between Trypanosoma brucei gambiense Groups 1 and 2 in Their Resistance to Killing by Trypanolytic Factor 1

Abstract

The three sub-species of Trypanosoma brucei are important pathogens of sub-Saharan Africa. T. b. brucei is unable to infect humans due to sensitivity to trypanosome lytic factors (TLF) 1 and 2 found in human serum. T. b. rhodesiense and T. b. gambiense are able to resist lysis by TLF. There are two distinct sub-groups of T. b. gambiense that differ genetically and by human serum resistance phenotypes. Group 1 T. b. gambiense have an invariant phenotype whereas group 2 show variable resistance. Previous data indicated that group 1 T. b. gambiense are resistant to TLF-1 due in-part to reduced uptake of TLF-1 mediated by reduced expression of the TLF-1 receptor (the haptoglobin-hemoglobin receptor (HpHbR)) gene. Here we investigate if this is also true in group 2 parasites. Isogenic resistant and sensitive group 2 T. b. gambiense were derived and compared to other T. brucei parasites. Both resistant and sensitive lines express the HpHbR gene at similar levels and internalized fluorescently labeled TLF-1 similar fashion to T. b. brucei. Both resistant and sensitive group 2, as well as group 1 T. b. gambiense, internalize recombinant APOL1, but only sensitive group 2 parasites are lysed. Our data indicate that, despite group 1 T. b. gambiense avoiding TLF-1, it is resistant to the main lytic component, APOL1. Similarly group 2 T. b. gambiense is innately resistant to APOL1, which could be based on the same mechanism. However, group 2 T. b. gambiense variably displays this phenotype and expression does not appear to correlate with a change in expression site or expression of HpHbR. Thus there are differences in the mechanism of human serum resistance between T. b. gambiense groups 1 and 2. The sub-species of Trypanosoma brucei are important pathogens of humans and animals in sub-Saharan Africa. T. b. brucei is not able to infect humans due to sensitivity to trypanosome lytic factors (TLF) containing the lytic protein apolipoprotein L1 (APOL1). T. b. gambiense is the most prevalent human infective sub-species, although there are two distinct sub-groups of T. b. gambiense that differ genetically and in terms of their human serum resistance phenotype stability. How they resist lysis by TLF is unknown. Previous data indicates that some group 1 T. b. gambiense parasites are able to avoid lysis due in part to reduced expression and activity of the gene encoding a TLF receptor (HpHbR). The authors showed that despite group 1 T. b gambiense displaying avoidance of some TLF particles, this sub-species group is resistant to the lytic protein of TLF, APOL1. This suggests that avoidance is not the complete story in this sub-species, as previously theorised. Group 2 T. b. gambiense is also innately resistant to APOL1 and there is no evidence of avoidance of TLF in resistant parasites. Group 2 T. b. gambiense variably displays the human serum resistance phenotype that does not appear to correlate with expression of HbHpR.