Søren Kragh Moestrup

Mechanism of Trypanosoma brucei gambiense resistance to human serum

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Mechanism of Trypanosoma brucei gambiense resistance to human serum. / Uzureau, Pierrick; Uzureau, Sophie; Lecordier, Laurence; Fontaine, Frédéric; Tebabi, Patricia; Homblé, Fabrice; Grélard, Axelle; Zhendre, Vanessa; Nolan, Derek P; Lins, Laurence; Crowet, Jean-Marc; Pays, Annette; Felu, Cécile; Poelvoorde, Philippe; Vanhollebeke, Benoit; Moestrup, Soren K; Lyngsø, Jeppe; Pedersen, Jan Skov; Mottram, Jeremy C; Dufourc, Erick J; Pérez-Morga, David; Pays, Etienne.

In: Nature, Vol. 501, No. 7467, 19.09.2013, p. 430-4.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Uzureau, P, Uzureau, S, Lecordier, L, Fontaine, F, Tebabi, P, Homblé, F, Grélard, A, Zhendre, V, Nolan, DP, Lins, L, Crowet, J-M, Pays, A, Felu, C, Poelvoorde, P, Vanhollebeke, B, Moestrup, SK, Lyngsø, J, Pedersen, JS, Mottram, JC, Dufourc, EJ, Pérez-Morga, D & Pays, E 2013, 'Mechanism of Trypanosoma brucei gambiense resistance to human serum', Nature, vol. 501, no. 7467, pp. 430-4. https://doi.org/10.1038/nature12516

APA

Uzureau, P., Uzureau, S., Lecordier, L., Fontaine, F., Tebabi, P., Homblé, F., Grélard, A., Zhendre, V., Nolan, D. P., Lins, L., Crowet, J-M., Pays, A., Felu, C., Poelvoorde, P., Vanhollebeke, B., Moestrup, S. K., Lyngsø, J., Pedersen, J. S., Mottram, J. C., ... Pays, E. (2013). Mechanism of Trypanosoma brucei gambiense resistance to human serum. Nature, 501(7467), 430-4. https://doi.org/10.1038/nature12516

CBE

Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F, Grélard A, Zhendre V, Nolan DP, Lins L, Crowet J-M, Pays A, Felu C, Poelvoorde P, Vanhollebeke B, Moestrup SK, Lyngsø J, Pedersen JS, Mottram JC, Dufourc EJ, Pérez-Morga D, Pays E. 2013. Mechanism of Trypanosoma brucei gambiense resistance to human serum. Nature. 501(7467):430-4. https://doi.org/10.1038/nature12516

MLA

Vancouver

Uzureau P, Uzureau S, Lecordier L, Fontaine F, Tebabi P, Homblé F et al. Mechanism of Trypanosoma brucei gambiense resistance to human serum. Nature. 2013 Sep 19;501(7467):430-4. https://doi.org/10.1038/nature12516

Author

Uzureau, Pierrick ; Uzureau, Sophie ; Lecordier, Laurence ; Fontaine, Frédéric ; Tebabi, Patricia ; Homblé, Fabrice ; Grélard, Axelle ; Zhendre, Vanessa ; Nolan, Derek P ; Lins, Laurence ; Crowet, Jean-Marc ; Pays, Annette ; Felu, Cécile ; Poelvoorde, Philippe ; Vanhollebeke, Benoit ; Moestrup, Soren K ; Lyngsø, Jeppe ; Pedersen, Jan Skov ; Mottram, Jeremy C ; Dufourc, Erick J ; Pérez-Morga, David ; Pays, Etienne. / Mechanism of Trypanosoma brucei gambiense resistance to human serum. In: Nature. 2013 ; Vol. 501, No. 7467. pp. 430-4.

Bibtex

@article{c969486eb4f74ee19b0060e8380199d6,
title = "Mechanism of Trypanosoma brucei gambiense resistance to human serum",
abstract = "The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.",
keywords = "Africa, Animals, Animals, Genetically Modified, Apolipoproteins, Cell Membrane, Cysteine Proteases, Haptoglobins, Hemoglobins, Hemolysis, Humans, Hydrophobic and Hydrophilic Interactions, Lipid Metabolism, Lipoproteins, HDL, Parasites, Protein Structure, Secondary, Serum, Trypanosoma brucei gambiense, Trypanosomiasis, African, Variant Surface Glycoproteins, Trypanosoma",
author = "Pierrick Uzureau and Sophie Uzureau and Laurence Lecordier and Fr{\'e}d{\'e}ric Fontaine and Patricia Tebabi and Fabrice Hombl{\'e} and Axelle Gr{\'e}lard and Vanessa Zhendre and Nolan, {Derek P} and Laurence Lins and Jean-Marc Crowet and Annette Pays and C{\'e}cile Felu and Philippe Poelvoorde and Benoit Vanhollebeke and Moestrup, {Soren K} and Jeppe Lyngs{\o} and Pedersen, {Jan Skov} and Mottram, {Jeremy C} and Dufourc, {Erick J} and David P{\'e}rez-Morga and Etienne Pays",
year = "2013",
month = sep,
day = "19",
doi = "10.1038/nature12516",
language = "English",
volume = "501",
pages = "430--4",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7467",

}

RIS

TY - JOUR

T1 - Mechanism of Trypanosoma brucei gambiense resistance to human serum

AU - Uzureau, Pierrick

AU - Uzureau, Sophie

AU - Lecordier, Laurence

AU - Fontaine, Frédéric

AU - Tebabi, Patricia

AU - Homblé, Fabrice

AU - Grélard, Axelle

AU - Zhendre, Vanessa

AU - Nolan, Derek P

AU - Lins, Laurence

AU - Crowet, Jean-Marc

AU - Pays, Annette

AU - Felu, Cécile

AU - Poelvoorde, Philippe

AU - Vanhollebeke, Benoit

AU - Moestrup, Soren K

AU - Lyngsø, Jeppe

AU - Pedersen, Jan Skov

AU - Mottram, Jeremy C

AU - Dufourc, Erick J

AU - Pérez-Morga, David

AU - Pays, Etienne

PY - 2013/9/19

Y1 - 2013/9/19

N2 - The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.

AB - The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic β-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.

KW - Africa

KW - Animals

KW - Animals, Genetically Modified

KW - Apolipoproteins

KW - Cell Membrane

KW - Cysteine Proteases

KW - Haptoglobins

KW - Hemoglobins

KW - Hemolysis

KW - Humans

KW - Hydrophobic and Hydrophilic Interactions

KW - Lipid Metabolism

KW - Lipoproteins, HDL

KW - Parasites

KW - Protein Structure, Secondary

KW - Serum

KW - Trypanosoma brucei gambiense

KW - Trypanosomiasis, African

KW - Variant Surface Glycoproteins, Trypanosoma

U2 - 10.1038/nature12516

DO - 10.1038/nature12516

M3 - Journal article

C2 - 23965626

VL - 501

SP - 430

EP - 434

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7467

ER -