A Haptoglobin-Hemoglobin Receptor Conveys Innate Immunity to
            <i>Trypanosoma brucei</i>
            in Humans

Vanhollebeke, Benoît; Muylder, Géraldine De; Nielsen, Marianne Jensby; Pays, Annette; Tebabi, Patricia; Dieu, Marc; Raes, Martine; Moestrup, Søren K.; Pays, Étienne

doi:10.1126/science.1156296

Cited by 219 publications

(329 citation statements)

References 26 publications

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“…Recent evidence confirms that the parasite vacuolar H + -ATPase endosomal acidification machinery is required for lysis by human serum (7). Receptor-mediated endocytosis of TLF1 is driven by a parasite haptoglobin-hemoglobin receptor, which binds Hpr-hemoglobin complexes, whereas TLF2 uptake occurs via an unknown, Hpr-independent mechanism (4,6,8,9).…”

mentioning

confidence: 84%

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

Thomson

Finkelstein

2015

Proc. Natl. Acad. Sci. U.S.A.

104

158

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Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation-selective macroscopic conductances in planar lipid bilayers. The conductances were highly sensitive to pH: their induction required acidic pH (pH 5.3), but their magnitude could be increased 3,000-fold upon alkalinization of the milieu (pK a = 7.1). We show that this phenomenon can be attributed to the association of APOL1 with the bilayer at acidic pH, followed by the opening of APOL1-induced cationselective channels upon pH neutralization. Furthermore, the conductance increase at neutral pH (but not membrane association at acidic pH) was prevented by the interaction of APOL1 with the serum resistance-associated protein, which is produced by T. brucei rhodesiense and prevents trypanosome lysis by APOL1. These data are consistent with a model of lysis that involves endocytic recycling of APOL1 and the formation of cation-selective channels, at neutral pH, in the parasite plasma membrane.APOL1 | apolipoprotein L-I | pH-gated channel | SRA | African trypanosome

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mentioning

confidence: 84%

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

Thomson

Finkelstein

2015

Proc. Natl. Acad. Sci. U.S.A.

104

158

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“…These include the haptoglobin‐hemglobin receptor (HpHbR), which plays a dual role in the uptake of HpHb as a source of haem and in the uptake of TLF particles 30. A recent structure of HpHbR from T. congolense 12 revealed an elongated, monomeric molecule, with a total length of 112 Å [Fig.…”

Section: Introductionmentioning

confidence: 99%

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

Higgins¹,

Carrington

2014

Protein Science

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Trypanosoma and Plasmodium species are unicellular, eukaryotic pathogens that have evolved the capacity to survive and proliferate within a human host, causing sleeping sickness and malaria, respectively. They have very different survival strategies. African trypanosomes divide in blood and extracellular spaces, whereas Plasmodium species invade and proliferate within host cells. Interaction with host macromolecules is central to establishment and maintenance of an infection by both parasites. Proteins that mediate these interactions are under selection pressure to bind host ligands without compromising immune avoidance strategies. In both parasites, the expansion of genes encoding a small number of protein folds has established large protein families. This has permitted both diversification to form novel ligand binding sites and variation in sequence that contributes to avoidance of immune recognition. In this review we consider two such parasite surface protein families, one from each species. In each case, known structures demonstrate how extensive sequence variation around a conserved molecular architecture provides an adaptable protein scaffold that the parasites can mobilise to mediate interactions with their hosts.

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“…This allows the parasite to steal the haem groups from Hb for incorporation into its own haemoproteins 5 . HpHbR is a 37-kDa receptor 5 structurally related to the glycophosphatidylinositol (GPI)-anchored trypanosomal VSGs 7 and the glutamic acid/alanine-rich protein, GARP, which replaces the VSGs in the tsetse midgut 8 . On the other hand, HpHbR is completely different from the mammalian Hp-Hb receptor, CD163 9 .…”

mentioning

confidence: 99%

“…Trypanosomes are deficient in haem biosynthesis and require uptake of exogenous haem 4 . Haem acquisition is mediated by the haptoglobin (Hp)-haemoglobin (Hb) receptor (HpHbR) located in the flagellar pocket of the parasite 5 . The receptor recognizes and takes up the Hp-Hb complex formed in the host's bloodstream when Hb is released from erythrocytes during haemolysis.…”

mentioning

confidence: 99%

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

et al. 2014

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Sleeping sickness is caused by trypanosome parasites, which infect humans and livestock in Sub-Saharan Africa. Haem is an important growth factor for the parasites and is acquired from the host by receptor-mediated uptake of haptoglobin (Hp)-haemoglobin (Hb) complexes. The parasite Hp-Hb receptor (HpHbR) is also a target for a specialized innate immune defence executed by trypanosome-killing lipoprotein particles containing an Hp-related protein in complex with Hb. Here we report the structure of the multimeric complex between human Hp-Hb and Trypanosoma brucei brucei HpHbR. Two receptors forming kinked three-helical rods with small head regions bind to Hp and the b-subunits of Hb (bHb), with one receptor at each end of the dimeric Hp-Hb complex. The Hb b-subunit haem group directly associates with the receptors, which allows for sensing of haem-containing Hp-Hb. The HpHbR-binding region of Hp is conserved in Hp-related protein, indicating an identical recognition of Hp-Hb and trypanolytic particles by HpHbR in human plasma.

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A Haptoglobin-Hemoglobin Receptor Conveys Innate Immunity to Trypanosoma brucei in Humans

Cited by 219 publications

References 26 publications

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

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

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

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

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