Trypanosoma brucei gambiense Group 1 Is Distinguished by a Unique Amino Acid Substitution in the HpHb Receptor Implicated in Human Serum Resistance

Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR function.罗德西亚布氏锥虫（Trypanosoma brucei rhodesiense，Tbr）与冈比亚布氏锥虫（T. b. gambiense，Tbg）是非洲人类锥虫病（Human African Trypanosomiasis，俗称昏睡病）的致病病原体，二者演化出不同机制以抵抗锥虫溶解因子（trypanosome lytic factors，TLFs）的活性——TLFs是人类血清中抵御其他非洲锥虫感染的先天免疫组分。在Tbr中，其溶细胞活性可被Tbr特异性的血清抗性相关蛋白（serum-resistance associated protein，SRA）所抑制。目前学界对Tbg的抗性机制了解尚浅，但已有假说认为其涉及结合珠蛋白-血红蛋白受体（haptoglobin haemoglobin receptor，HpHbR）的活性改变与表达调控。已有研究证实，在布氏锥虫种复合体中对人类血清敏感的布氏布氏锥虫（T.b. brucei，Tbb）体内，HpHbR可介导TLF-1的内化过程。本研究通过在全面的地理与分类学框架下评估HpHbR的遗传变异，发现210位亮氨酸被丝氨酸取代的单氨基酸变异，在分布最广泛的Tbg亚型（Tbg 1群）中高度保守，且该变异不存在于其他相关类群；这些相关类群要么对人类血清敏感（如Tbb），要么通过其他机制获得血清抗性（如Tbr与Tbg 2群）。我们推测该单氨基酸变异可降低TLF的摄取效率，因此可能在赋予Tbg 1群血清抗性的过程中发挥关键作用。与之相反，Tbg 2群分离株与Tbb/Tbr的HpHbR序列具有相似性，这进一步证明Tbg 2群的血清抗性可能不依赖于HpHbR的功能。