Identification of the trypanocidal factor in normal human serum: high density lipoprotein.

Rifkin, Mary R.

doi:10.1073/pnas.75.7.3450

Cited by 171 publications

(80 citation statements)

References 17 publications

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“…The latter showed the lowest transmigration rate. In vivo, T. b. brucei is not able to survive in the human bloodstream because of its sensitivity to trypanolytic factors in human serum (Hajduk et al, 1989;Rifkin, 1978). If the trypanolytic factor is absent, non-human pathogenic trypanosomes can cause life-threatening infections, as shown in a case report from India (Vanhollebeke et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

An optimized in vitro blood–brain barrier model reveals bidirectional transmigration of African trypanosome strains

et al. 2011

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The transmigration of African trypanosomes across the human blood-brain barrier (BBB) is the critical step during the course of human African trypanosomiasis. The parasites Trypanosoma brucei gambiense and T. b. rhodesiense are transmitted to humans during the bite of tsetse flies. Trypanosomes multiply within the bloodstream and finally invade the central nervous system (CNS), which leads to the death of untreated patients. This project focused on the mechanisms of trypanosomal traversal across the BBB. In order to establish a suitable in vitro BBB model for parasite transmigration, different human cell lines were used, including ECV304, HBMEC and HUVEC, as well as C6 rat astrocytes. Validation of the BBB models with Escherichia coli HB101 and E. coli K1 revealed that a combination of ECV304 cells seeded on Matrigel as a semisynthetic basement membrane and C6 astrocytes resulted in an optimal BBB model system. The BBB model showed selective permeability for the pathogenic E. coli K1 strain, and African trypanosomes were able to traverse the optimized ECV304-C6 BBB efficiently. Furthermore, coincubation indicated that paracellular macrophage transmigration does not facilitate trypanosomal BBB traversal. An inverse assembly of the BBB model demonstrated that trypanosomes were also able to transmigrate the optimized ECV304-C6 BBB backwards, indicating the relevance of the CNS as a possible reservoir of a relapsing parasitaemia. INTRODUCTIONHuman African trypanosomiasis is a vector-borne parasitic disease, which currently causes about 10 000 deaths each year. At the end of the last century the number of lethal cases was estimated as up to 300 000, according to WHO data. The disease threatens over 60 million people of 36 African nations, reaching lethality of 100 % without treatment (WHO, 2010). The parasites, called trypanosomes, are transmitted during a blood meal of tsetse flies of the Glossina genus and can infect humans as well as cattle. Trypanosoma brucei brucei is one of the causative agents of Nagana, a severe cattle disease, which hampers intensive cattle farming in endemic areas (Steverding, 2008). T. b. gambiense and T. b. rhodesiense are human pathogens and multiply within the blood circulation system. Therein, the parasites evade the host immune system by different strategies, for instance by switching their surface-coat antigens (Dubois et al., 2005). As the disease progresses, the parasites infect the central nervous system (CNS), leading to the severe outcome of the disease. Once inside the CNS, parasites are hardly reached by drugs or by the immune system. Depending on the trypanosome subspecies the parasites transmigrate through the human blood-brain barrier (BBB) within a few weeks (T. b. rhodesiense), some months or even years (T. b. gambiense). So far, the invasion into the CNS of African trypanosomes is poorly understood (Grab & Kennedy, 2008). It has been shown that secreted proteases (Nikolskaia et al., 2006(Nikolskaia et al., , 2008, in the case of T. b. rhodesiense, and the composition of ...

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Section: Discussionmentioning

confidence: 99%

An optimized in vitro blood–brain barrier model reveals bidirectional transmigration of African trypanosome strains

et al. 2011

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“…Trypanolytic activity is split between two subfractions of high-density lipoprotein, called trypanosome lytic factors (TLF1 and TLF2), that both contain haptoglobin-related protein (Hpr) and apolipoprotein L-1 (APOL1) (1)(2)(3)(4). Lysis follows the endocytosis of TLF by the parasite and is blocked by weak bases, indicating that acidification of endosomes and/or the lysosome is required (5,6).…”

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confidence: 99%

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.

107

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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“…The resistance of humans to infection by T. b. brucei is a consequence of an innate, protective class of human HDLs containing apoL-1, Hpr, apoA-1, and apoA-II (23,50,57,59,60,65,69). African trypanosomes that cause human sleeping sickness circumvent the cytotoxic activity of this HDL subclass.…”

Section: Discussionmentioning

confidence: 99%

“…This innate protection is provided by trypanolytic activity found in normal human blood and also in the blood of most apes and Old World monkeys (24,31,46,56). The trypanosome lytic factor (TLF) is a minor subfraction of heterogeneous human high-density lipoprotein (HDL) particles containing apoliprotein A-I (apoA-I), apoliprotein A-II (apoA-II), apolipoprotein L-I (apoL-I), and haptoglobin-related protein (Hpr) (23,29,38,45,48,49,50,51,52,57,59,60,64,65,69). The mechanism of TLF killing of T. b. brucei has been controversial.…”

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confidence: 99%

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

et al. 2006

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Identification of the trypanocidal factor in normal human serum: high density lipoprotein.

Cited by 171 publications

References 17 publications

An optimized in vitro blood–brain barrier model reveals bidirectional transmigration of African trypanosome strains

An optimized in vitro blood–brain barrier model reveals bidirectional transmigration of African trypanosome strains

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

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

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