The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins1,2,3,4. APOL1 kills the bloodstream parasite Trypanosoma brucei brucei, but not the human sleeping sickness agents T.b. rhodesiense and T.b. gambiense 3. We considered the possibility that intracellular members of the APOL1 family, against which extracellular trypanosomes could not have evolved resistance, could kill pathogenic T. brucei subspecies. Here we show that recombinant APOL3 (rAPOL3) kills all African trypanosomes, including T.b. rhodesiense, T.b. gambiense and the animal pathogens Trypanosoma evansi, Trypanosoma congolense and Trypanosoma vivax. However, rAPOL3 did not kill more distant trypanosomes such as Trypanosoma theileri or Trypanosoma cruzi. This trypanolytic potential was partially shared by rAPOL1 from Papio papio (rPpAPOL1). The differential killing ability of rAPOL3 and rAPOL1 was associated with a distinct dependence on acidic pH for activity. Due both to its instability and toxicity when injected into mice, rAPOL3 cannot be used for the treatment of infection, but an experimental rPpAPOL1 mutant inspired by APOL3 exhibited enhanced trypanolytic activity in vitro and the ability to completely inhibit T.b. gambiense infection in mice. We conclude that pH dependence influences the trypanolytic potential of rAPOLs.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vanhollebeke, B. & Pays, E. The function of apolipoproteins L. Cell. Mol. Life Sci. 63, 1937–1944 (2006).
Hu, C. A., Klopfer, E. I. & Ray, P. E. Human apolipoprotein L1 (ApoL1) in cancer and chronic kidney disease. FEBS Lett. 586, 947–955 (2012).
Pays, E., Vanhollebeke, B., Uzureau, P., Lecordier, L. & Pérez-Morga, D. The molecular arms race between African trypanosomes and humans. Nat. Rev. Microbiol. 12, 575–584 (2014).
Uzureau, S. et al. Apolipoproteins L control cell death triggered by TLR3/TRIF signaling in dendritic cells. Eur. J. Immunol. 46, 1854–1866 (2016).
Vanhamme, L. et al. Apolipoprotein L-I is the trypanosome lytic factor of human serum. Nature 422, 83–87 (2003).
Pérez-Morga, D. et al. Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes. Science 309, 469–472 (2005).
Vanwalleghem, G. et al. Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1. Nat. Commun. 6, 8078 (2015).
Greene, A. S. & Hajduk, S. L. Trypanosome lytic factor-1 initiates oxidation-stimulated osmotic lysis of Trypanosoma brucei brucei. J. Biol. Chem. 291, 3063–3075 (2016).
Shimamura, M., Hager, K. M. & Hajduk, S. L. The lysosomal targeting and intracellular metabolism of trypanosome lytic factor by Trypanosoma brucei brucei. Mol. Biochem. Parasitol. 115, 227–237 (2001).
Lecordier, L. et al. Identification of Trypanosoma brucei components involved in trypanolysis by normal human serum. Mol. Microbiol. 94, 625–636 (2014).
Thomson, R. & Finkelstein, A. Human trypanolytic factor APOL1 forms pH-gated cation-selective channels in planar lipid bilayers: relevance to trypanosome lysis. Proc. Natl Acad. Sci. USA 112, 2894–2899 (2015).
Alsford, S., Currier, R. B., Guerra-Assunção, J. A., Clark, T. G. & Horn, D. Cathepsin-L can resist lysis by human serum in Trypanosoma brucei brucei. PLoS Pathog. 10, e1004130 (2014).
Xong, H. V. et al. A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense. Cell 95, 839–846 (1998).
Uzureau, P. et al. Mechanism of Trypanosoma gambiense resistance to human serum. Nature 501, 430–434 (2013).
Capewell, P. et al. The TgsGP gene is essential for resistance to human serum in Trypanosoma brucei gambiense. PLoS Pathog. 9, e1003686 (2013).
Lecordier, L. et al. C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. PLoS Pathog. 5, e1000685 (2009).
Genovese, G. et al. Association of trypanolytic apoL1 variants with kidney disease in African-Americans. Science 329, 841–845 (2010).
Thomson, R., Molina-Portela, P., Mott, H., Carrington, M. & Raper, J. Hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective African trypanosomes. Proc. Natl Acad. Sci. USA 106, 19509–19514 (2009).
Page, N. M., Butlin, D. J., Lomthaisong, K. & Lowry, P. J. The human apolipoprotein L gene cluster: identification, classification, and sites of distribution. Genomics 74, 71–78 (2001).
Bruggeman, L. A. et al. Plasma apolipoprotein L1 levels do not correlate with CKD. J. Am. Soc. Nephrol. 25, 634–644 (2014).
Vanhollebeke, B., Lecordier, L., Perez-Morga, D., Amiguet-Vercher, A. & Pays, E. Human serum lyses Trypanosoma brucei by triggering uncontrolled swelling of the parasite lysosome. J. Eukaryot. Microbiol. 54, 448–451 (2007).
Pays, E. et al. The trypanolytic factor of human serum. Nat. Rev. Microbiol. 4, 477–486 (2006).
Dutoya, S. et al. A novel C-terminal kinesin is essential for maintaining functional acidocalcisomes in Trypanosoma brucei. J. Biol. Chem. 276, 49117–49124 (2001).
Barrera, F. N. et al. Roles of carboxyl groups in the transmembrane insertion of peptides. J. Mol. Biol. 413, 359–371 (2011).
Willyard, C. Putting sleeping sickness to bed. Nat. Med. 17, 14–17 (2011).
Raper, J. & Friedman, D. J. Parasitology: molecular one-upmanship. Nature 501, 322–323 (2013).
Kageruka, P. et al. Infectivity of Trypanosoma (Trypanozoon) brucei gambiense for baboons (Papio hamadryas, Papio papio). Ann. Soc. Belg. Med. Trop. 71, 39–46 (1991).
Cooper, A. et al. A primate APOL1 variant that kills Trypanosoma brucei gambiense. PLoS Negl. Trop. Dis. 10, e0004903 (2016).
Radwanska, M. et al. Novel primer sequences for a polymerase chain reaction-based detection of Trypanosoma brucei gambiense. Am. J. Trop. Med. Hyg. 67, 289–295 (2002).
Pyana Pati, P. et al. Melarsoprol sensitivity profile of Trypanosoma brucei gambiense isolates from cured and relapsed sleeping sickness patients from the Democratic Republic of the Congo. PLoS Negl. Trop. Dis. 8, e3212 (2014).
The authors thank A. Kremer (Ghent) for the FIB–SEM acquisitions. This work was supported by the European Research Council (ERC 669007-APOLs), the Interuniversity Attraction Poles Programme–Belgian Science Policy (PAI P7-41) and the PDR-FNRS (PDR T.0159.13). The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and Wallonia.
The authors declare no competing financial interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Fontaine, F., Lecordier, L., Vanwalleghem, G. et al. APOLs with low pH dependence can kill all African trypanosomes. Nat Microbiol 2, 1500–1506 (2017). https://doi.org/10.1038/s41564-017-0034-1
Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes
Proceedings of the National Academy of Sciences (2020)
The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection
The FEBS Journal (2020)
APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin
Cell Reports (2020)
Kidney International Reports (2019)