The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy

Jennings, F. W.; Whitelaw, D.D.; Holmes, P.H.; Chizyuka, H. G. B.; Urquhart, G. M.

doi:10.1016/0020-7519(79)90089-4

Cited by 109 publications

(46 citation statements)

References 7 publications

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“…Correct identification of the disease stage of patients is essential for successful treatment in order to prevent relapsing parasitaemia. As shown in a rat infection model, the CNS can be a source of reinfection with parasites after clearance of bloodstream trypanosomes in consequence of treatment with drugs that cannot enter the CNS (Jennings et al, 1979). Results of the present study showed that trypanosomes traverse an inverse ECV304-C6 BBB model system with similar transmigration rates as in the normal BBB model.…”

Section: Discussionsupporting

confidence: 66%

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: Discussionsupporting

confidence: 66%

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

et al. 2011

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“…This has been shown in human African trypanosomiasis (= HAT) by CALWELL (1937) and bv various authors : JENNINGS et al, 1979~~~~~~ et al:, 1981, i982) …”

Section: Introduction Laboratory Methodsmentioning

confidence: 61%

“…Hence a critical and patient long term follow-up of treated trypanosome-infected hosts is essential before cure is declared. Improvement in tissue techniques permitted visualization of trypanosomes, particularly with immunofluorescence (POL-TERA et al, 1980 and electron microscopy (RUDIN et al, 1983), organ transfer experiments (JENNINGS et al, 1979) and tissue elution techniques (MULUMBA & WBRY, 1983). It appears that trypanosomes shift from a choroid plexus and meningeal invasion to intracerebral, extracellular-interstitial y;*:zation in relapse cases (POLTERA er al., 1981, Tfiese "persister" trypanosomes have been found interstitiallv bv EM in several chemotheraneutic models (RCDIN-et al, 1983) and they appear m&pho-logically to be perfectly viable.…”

Section: Discussionmentioning

confidence: 99%

Immunopathological aspects of trypanosomal meningoencephalitis in vervet monkeys after relapse following BerenilR treatment

Poltera

Sayer²,

Brighouse

et al. 1985

Transactions of the Royal Society of Tropical Medicine and Hygi

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Four quarantined vervet monkeys were treated with intramuscular BerenilR in patent CNS infection after experimental trypanosome inoculation with Typanosoma brucei rhodesiense or T. brucei brucei. All four animals relapsed in the post-therapeutic survival time of 37 to 209 days when they had fully developed me~ngoencepha~tis in histological sections with the presence of interstitial intracerebral trypanosomes, which were confirmed in two monkeys by electron microscopy. In both, sequential samples of the serum and cerebrospinal fluid were analysed for circulating immune complexes, immunoglobulins and albumin. From these results the intracerebral IgG synthesis and the impairment of the blood-brain-barrier were calculated, both being present in advanced infection. Circulating immune complexes were present in the serum, but could not be demonstrated in the cerebrospinal fluid. The monkey model therefore permits the study of various aspects of cerebral trypanosomiasis. BerenilR treatment is inefficient in patent CNS infection and leads to a protracted, less virulent disease course with terminal men~g~ncephalitis and intracerebral "persister" trypanosomes. This drug-induced trypanosome shift with me~ngoencepha~tis could be used for chemotherapeutic purposes to test new compounds in late stage disease.

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“…It has been established that treatment of experimental T. b. brucei infection in animals becomes less effective as time interval between infection and treatment increases [20]. A possible explanation for this is the presence of trypanosomes in drug-inaccessible sites like the brain [21]. Treatment was initiated 8 days PI, which was 3 days post-confirmation of parasitemia.…”

Section: Discussionmentioning

confidence: 99%

Anti-trypanosomal activity of secnidazole in vitro and in vivo

Eke¹,

Eze²,

Ezeudu³

et al. 2017

Trop. J. Pharm Res

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The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy

Cited by 109 publications

References 7 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

Immunopathological aspects of trypanosomal meningoencephalitis in vervet monkeys after relapse following BerenilR treatment

Anti-trypanosomal activity of secnidazole in vitro and in vivo

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