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

Faulkner, Sara D.; Oli, Monika W.; Kieft, Rudo; Cotlin, Laura F.; Widener, Justin; Shiflett, April M.; Cipriano, Michael J.; Pacocha, Sarah E.; Birkeland, Shanda R.; Hajduk, Stephen L.; McArthur, Andrew G.

doi:10.1128/ec.00116-06

Cited by 20 publications

(31 citation statements)

References 74 publications

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“…This raises the possibility that TLF-1 resistance in T. b. gambiense might be caused by the evolution of another TLF-1 neutralizing factor or that resistance could result from evasion of TLF-1 uptake. Group 1 T. b. gambiense has proven to be largely intractable to genetic manipulation leading us to develop a model for SRA-independent resistance to TLF-1 in T. b. brucei (25). Results presented here show that the loss of expression of the Hp/Hb receptor, encoded by the TbbHpHbR gene, can be selected for in T. b. brucei.…”

Section: Discussionmentioning

confidence: 92%

Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor

Kieft

Capewell²,

Turner³

et al. 2010

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

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110

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Human innate immunity against most African trypanosomes, including Trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum HDL, called trypanosome lytic factor-1 (TLF-1). This HDL contains two primate specific proteins, apolipoprotein L-1 and haptoglobin (Hp)-related protein, as well as apolipoprotein A-1. These assembled proteins provide a powerful defense against trypanosome infection. Trypanosoma brucei rhodesiense causes human African sleeping sickness because it has evolved an inhibitor of TLF-1, serum resistance-associated (SRA) protein. Trypanosoma brucei gambiense lacks the SRA gene, yet it infects humans. As transfection of T. b. gambiense (group 1) is not possible, we initially used in vitro-selected TLF-1-resistant T. b. brucei to examine SRA-independent mechanisms of TLF-1 resistance. Here we show that TLF-1 resistance in T. b. brucei is caused by reduced expression of the Hp/Hb receptor gene (TbbHpHbR). Importantly, T. b. gambiense (group 1) also showed a marked reduction in uptake of TLF-1 and a corresponding decrease in expression of T. b. gambiense Hp/Hb receptor (TbgHpHbR). Ectopic expression of TbbHpHbR in TLF-1-resistant T. b. brucei rescued TLF-1 uptake, demonstrating that decreased TbbHpHbR expression conferred TLF-1 resistance. Ectopic expression of TbgHpHbR in TLF-1-resistant T. b. brucei failed to rescue TLF-1 killing, suggesting that coding sequence changes altered Hp/Hb receptor binding affinity for TLF-1. We propose that the combination of coding sequence mutations and decreased expression of TbgHpHbR directly contribute to parasite evasion of human innate immunity and infectivity of group 1 T. b. gambiense.African trypanosomes | haptoglobin/hemoglobin receptor | innate immunity | human serum resistance

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Section: Discussionmentioning

confidence: 92%

Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor

Kieft

Capewell²,

Turner³

et al. 2010

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

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110

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“…The presence of expected PCR product of 670bp or multiples thereof confirms the presence of SRA gene. (Faulkner et al, 2006;Pays et al, 2006). These two sub-species are largely indistinguishable from T. b. brucei except for their resistance to the cytotoxic action of human serum and their ability to infect humans.…”

Section: Confirmation Of T Brucei Subgroupmentioning

confidence: 98%

“…To directly investigate this possibility, a study was carried out elsewhere for in vitro selection to generate human HDL-resistant T. b. brucei. The results showed that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs (Faulkner et al, 2006 (Van Nieuwenhove et al, 2001). The overlap in distribution of both of these pathogenic sub-species can result in erroneous diagnoses since both trypanosome sub-species are morphologically identical, and the currently available serologic techniques have low specificity (Radwanska et al, 2002).…”

Section: Confirmation Of T Brucei Subgroupmentioning

confidence: 99%

Susceptibility of Simulium damnosum complex larvae to temephos in the Tukuyu onchocerciasis focus, southwest Tanzania

Kalinga

Mweya²,

Barro³

et al. 2007

Tanzania J Hlth Res

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Tukuyu onchocerciasis focus was earmarked for vector control using insecticide against larval stages. Susceptibility tests of mature larvae of Simulium damnosum s.l. vectors to temephos insecticide were carried out before and after two years of insecticide treatment of rivers within Tukuyu onchocerciasis focus, south-western Tanzania. The tests were done in 1999/2000 and 2004 using WHO standard methods. Mature larvae were exposed to 9 concentrations of temephos active ingredient, from the weakest 0.00975mg/litre to the strongest of 2.5mg/l. Each test concentration and control was run in duplicates of 25 larvae each, set for three hours in a cool temperature. After incubation, test solution was discarded and larval condition checked. Numbers of larvae in each category were recorded and used to determine mortality rate for each concentration as well as for the LC 50 and LC 95 . A total of 1,666 larvae were tested, 942 during the pre-and 724 post-treatment. Results showed that both pre and post-treatment samples were susceptible, attaining 100% mortality at the diagnostic dose of 1.25mg/l, and LC 50 between 0.129-0.34mg/l pre -and 0.144-0.211 mg/l (95% CI, P<0.05) post-treatment. These values fall within the standard diagnostic dose of ≤0.4mg/l for susceptible S. damnosum s.l populations. It was concluded that the endemic S. damnosum population was susceptible to temephos before and after two years of intermittent field application. Temephos was thus recommended for continued use in onchocerciasis vector control in the Tukuyu focus, to complement Community Directed Treatment with Ivermectin, but close monitoring of vector susceptibility should be done.

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“…A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to T. b. brucei but not the human sleeping sickness parasite T. b. rhodesiense and T. b. gambiense (Faulkner et al, 2006;Pays et al, 2006). These two sub-species are largely indistinguishable from T. b. brucei except for their resistance to the cytotoxic action of human serum and their ability to infect humans.…”

Section: Discussionmentioning

confidence: 99%

“…To directly investigate this possibility, a study was carried out elsewhere for in vitro selection to generate human HDL-resistant T. b. brucei. The results showed that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs (Faulkner et al, 2006). These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of the Trypanosoma brucei rhodesiense isolates from Tanzania using serum resistance associated gene as molecular marker

Kibona

Picozzi²,

Matemba³

et al. 2007

Tanzania J Hlth Res

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Serum resistance associated (SRA) gene has been found to confer resistance to the innate trypanolytic factor (TLF) found in normal human serum; thus allowing Trypanosoma brucei brucei to survive exposure to normal human serum. This study was carried out to examine the presence of SRA gene and identify the origin of T. b. rhodesiense isolates from three districts in Tanzania, namely Kibondo, Kasulu and Urambo. Twenty-six T. b. rhodesiense isolates and two references T. b. rhodesiense isolates from Kenya were examined for SRA gene using simple Polymerase Chain Reaction technique. The gene was found to be present in all 26 T. b. rhodesiense isolates including the two references isolates from Kenya. The SRA gene was confirmed to be specific to T. b. rhodesiense since it could not be amplified from all other Trypanozoon including T. b. gambiense; and gave an amplified fragment of the expected size (3.9kb), confirming that all these isolates were T. b. rhodesiense of the northern variant. Although the geographic distributions of T. b. gambiense and T. b. rhodesiense are clearly localized to west/central Africa and eastern Africa, respectively, natural movement of people and recent influx of large number of refugees into Tanzania from the Democratic Republic of Congo, could have brought T. b. gambiense in western Tanzania. The overlap in distribution of both of these pathogenic sub-species could result in erroneous diagnoses since both trypanosome sub-species are morphologically identical, and currently serologic methods have low specificity. Both the susceptible and resistant T.b. rhodesiense isolates possessed the SRA gene suggesting that there is no correlation between drug resistance and presence of SRA gene. The use of SRA gene helps to confirm the identity and diversity of some of the isolates resistant to various drugs.

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

Cited by 20 publications

References 74 publications

Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor

Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor

Susceptibility of <i>Simulium damnosum</i> complex larvae to temephos in the Tukuyu onchocerciasis focus, southwest Tanzania

Characterisation of the <i>Trypanosoma brucei rhodesiense</i> isolates from Tanzania using serum resistance associated gene as molecular marker

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