Adaptation of T rypanosoma rhodesiense to hypohaptoglobinaemic serum requires transcription of the APOL 1 resistance gene in a RNA polymerase I locus

Summary Human apolipoprotein L 1 ( APOL 1) kills African trypanosomes except T rypanosoma rhodesiense and T rypanosoma gambiense , the parasites causing sleeping sickness. APOL 1 uptake into trypanosomes is favoured by its association with the haptoglobin‐related protein–haemoglobin complex, which binds to the parasite surface receptor for haptoglobin–haemoglobin. As haptoglobin–haemoglobin can saturate the receptor, APOL 1 uptake is increased in haptoglobin‐poor (hypohaptoglobinaemic) serum ( HyHS ). While T . rhodesiense resists APOL 1 by RNA polymerase I (pol‐ I )‐mediated expression of the serum resistance‐associated ( SRA ) protein, T . gambiense resists by pol‐ II ‐mediated expression of the T . gambiense ‐specific glycoprotein ( TgsGP ). Moreover, in T . gambiense resistance to HyHS is linked to haptoglobin–haemoglobin receptor inactivation by mutation. We report that unlike T . gambiense , T . rhodesiense possesses a functional haptoglobin–haemoglobin receptor, and that like T . gambiense experimentally provided with active receptor, this parasite is killed in HyHS because of receptor‐mediated APOL 1 uptake. However, T . rhodesiense could adapt to low haptoglobin by increasing transcription of SRA . When assayed in Trypanosoma brucei , resistance to HyHS occurred with pol‐ I ‐, but not with pol‐ II ‐mediated SRA expression. Similarly, T . gambiense provided with active receptor acquired resistance to HyHS only when TgsGP was moved to a pol‐ I locus. Thus, transcription by pol‐ I favours adaptive gene regulation, explaining the presence of SRA in a pol‐ I locus.