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

<div><p><i>Trypanosoma brucei rhodesiense</i> (<i>Tbr</i>) and <i>T. b. gambiense</i> (<i>Tbg</i>), 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 <i>Tbr</i>, lytic activity is suppressed by the <i>Tbr-</i>specific serum-resistance associated (SRA) protein. The mechanism in <i>Tbg</i> 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 <i>T.b. brucei</i> (<i>Tbb</i>), a member of the <i>T. brucei</i> species complex that is susceptible to human serum. By evaluating the genetic variability of <i>HpHbR</i> 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 <i>Tbg</i> (<i>Tbg</i> group 1) and not found in related taxa, which are either human serum susceptible (<i>Tbb</i>) or known to resist lysis via an alternative mechanism (<i>Tbr</i> and <i>Tbg</i> 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 <i>Tbg</i> group 1. In contrast, similarity in <i>HpHbR</i> sequence among isolates of <i>Tbg</i> group 2 and <i>Tbb</i>/<i>Tbr</i> provides further evidence that human serum resistance in <i>Tbg</i> group 2 is likely independent of HpHbR function.</p>