The TgsGP Gene Is Essential for Resistance to Human Serum in Trypanosoma brucei gambiense

Abstract

Trypanosoma brucei gambiense causes 97% of all cases of African sleeping sickness, a fatal disease of sub-Saharan Africa. Most species of trypanosome, such as T. b. brucei, are unable to infect humans due to the trypanolytic serum protein apolipoprotein-L1 (APOL1) delivered via two trypanosome lytic factors (TLF-1 and TLF-2). Understanding how T. b. gambiense overcomes these factors and infects humans is of major importance in the fight against this disease. Previous work indicated that a failure to take up TLF-1 in T. b. gambiense contributes to resistance to TLF-1, although another mechanism is required to overcome TLF-2. Here, we have examined a T. b. gambiense specific gene, TgsGP, which had previously been suggested, but not shown, to be involved in serum resistance. We show that TgsGP is essential for resistance to lysis as deletion of TgsGP in T. b. gambiense renders the parasites sensitive to human serum and recombinant APOL1. Deletion of TgsGP in T. b. gambiense modified to uptake TLF-1 showed sensitivity to TLF-1, APOL1 and human serum. Reintroducing TgsGP into knockout parasite lines restored resistance. We conclude that TgsGP is essential for human serum resistance in T. b. gambiense.

Evolution of the primate trypanolytic factor APOL1

“…None of the other animal-infective trypanosomes have acquired SRA, and thus, they cannot infect humans. In contrast, human-infective T. b gambiense has evolved different mechanisms of resistance to TLF (13)(14)(15) and is resistant to G1 and G2 sera in vitro (1). The dramatic increase in frequency of G1 in West Africa, despite the presence in the gene pool of the more effective T. b. rhodesiense killer G2, hints that the two alleles were selected in response to more than one pathogen.…”

“…Human and gorilla sera protect against Trypanosoma brucei brucei, whereas baboon sera protect against T. b. brucei, Trypanosoma brucei rhodesiense, and potentially, Trypanosoma brucei gambiense (8,9). Human-infective T. b. rhodesiense, which causes acute African sleeping sickness, arose from animal-infective T. b. brucei through the evolution of a virulence factor called serum resistance-associated protein (SRA) (10) that binds to (11) and prevents human APOL1-mediated lysis (12), whereas T. b. gambiense evolved different mechanisms to neutralize human APOL1 (13)(14)(15).…”

Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: Relevance to trypanosome lysis

“…Whereas multifactorial mechanisms were proposed to account for resistance of T. b. gambiense to human serum (13)(14)(15)(16), resistance in the case of T. b. rhodesiense is determined by the parasite's serum resistance-associated (SRA) protein, which localizes to parasite endosomes and binds to APOL1 under acidic conditions (10,17). Primate APOL1 orthologs, and two African human APOL1 variants, contain mutations in the C-terminal SRA-binding site that reduce binding affinity for SRA, allowing these variants to lyse SRA-producing trypanosomes (18)(19)(20).…”

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

“…rhodesiense) and Trypanosoma brucei gambiense (T.b. gambiense) express resistance proteins counteracting apolipoprotein L1 activity enabling these parasite strains to evade the lethal action of TLF particles [22][23][24][25] . T.b.…”