Regulation of Parasitaemia in Mice Infected with Trypanosoma brucei

Black, Samuel J.; Sendashonga, Cyriaque N.; O’Brien, Catherine; Borowy, N.K.; Naessens, M.; Webster, Paul; Murray, M.

doi:10.1007/978-3-642-70538-0_5

Cited by 47 publications

(39 citation statements)

References 54 publications

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“…Differentiation to the stumpy form is thought to be one mechanism contributing to the control of T. brucei parasite density in mammalian hosts (Balber, 1972; Black et al ., 1985; Vassella et al ., 1997). Therefore, we hypothezised that null mutants might exhibit accelerated differentiation and consequently reduced peak parasitaemia in infected animals.…”

Section: Resultssupporting

confidence: 83%

Deletion of a novel protein kinase with PX and FYVE‐related domains increases the rate of differentiation of Trypanosoma brucei

Vassella

Kramer

Turner

et al. 2001

Molecular Microbiology

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SummaryGrowth control of African trypanosomes in the mammalian host is coupled to differentiation of a non-dividing life cycle stage, the stumpy bloodstream form. We show that a protein kinase with novel domain architecture is important for growth regulation. Zinc finger kinase (ZFK) has a kinase domain related to RAC and S6 kinases flanked by a FYVErelated zinc finger and a phox (PX) homology domain. To investigate the function of the kinase during cyclical development, a stable transformation procedure for bloodstream forms of differentiationcompetent (pleomorphic) Trypanosoma brucei strains was established. Deletion of both allelic copies of ZFK by homologous recombination resulted in reduced growth of bloodstream-form parasites in culture, which was correlated with an increased rate of differentiation to the non-dividing stumpy form. Growth and differentiation rates were returned to wild-type level by ectopic ZFK expression. The phenotype is stage-specific, as growth of procyclic (insect form) trypanosomes was unaffected, and Dzfk/Dzfk clones were able to undergo full cyclical development in the tsetse fly vector. Deletion of ZFK in a differentiation-defective (monomorphic) strain of T. brucei did not change its growth rate in the bloodstream stage. This suggests a function of ZFK associated with the trypanosomes' decision between either cell cycle progression, as slender bloodstream form, or differentiation to the non-dividing stumpy form.

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Section: Resultssupporting

confidence: 83%

Deletion of a novel protein kinase with PX and FYVE‐related domains increases the rate of differentiation of Trypanosoma brucei

Vassella

Kramer

Turner

et al. 2001

Molecular Microbiology

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“…These observations suggest that besides antibodies, additional host factors can contribute to parasite control. During the chronic phase of trypanosomiasis, the continuous interplay between the parasite and its host's immune system results in infection-associated pathology, including anemia [14]–[20], [31]–[35]. Despite the importance of anemia, the exact mechanisms underlying its induction remained unsolved [35].…”

Section: Discussionmentioning

confidence: 99%

The Role of B-cells and IgM Antibodies in Parasitemia, Anemia, and VSG Switching in Trypanosoma brucei–Infected Mice

et al. 2008

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African trypanosomes are extracellular parasitic protozoa, predominantly transmitted by the bite of the haematophagic tsetse fly. The main mechanism considered to mediate parasitemia control in a mammalian host is the continuous interaction between antibodies and the parasite surface, covered by variant-specific surface glycoproteins. Early experimental studies have shown that B-cell responses can be strongly protective but are limited by their VSG-specificity. We have used B-cell (µMT) and IgM-deficient (IgM−/−) mice to investigate the role of B-cells and IgM antibodies in parasitemia control and the in vivo induction of trypanosomiasis-associated anemia. These infection studies revealed that that the initial setting of peak levels of parasitemia in Trypanosoma brucei–infected µMT and IgM−/− mice occurred independent of the presence of B-cells. However, B-cells helped to periodically reduce circulating parasites levels and were required for long term survival, while IgM antibodies played only a limited role in this process. Infection-associated anemia, hypothesized to be mediated by B-cell responses, was induced during infection in µMT mice as well as in IgM−/− mice, and as such occurred independently from the infection-induced host antibody response. Antigenic variation, the main immune evasion mechanism of African trypanosomes, occurred independently from host antibody responses against the parasite's ever-changing antigenic glycoprotein coat. Collectively, these results demonstrated that in murine experimental T. brucei trypanosomiasis, B-cells were crucial for periodic peak parasitemia clearance, whereas parasite-induced IgM antibodies played only a limited role in the outcome of the infection.

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“…Owing to antigenic variation, the course of infection is characterized by parasitic waves, which peak every 8 to 10 days; untreated, the infection is lethal. Although the decline of parasite density is attributed to the appearance of specific antibodies, 1,2 immunosuppressed animals also show a regular increase and decrease in parasite numbers, [3][4][5] and this behavior is even observed in vitro, if culture media are replaced at regular intervals. 6 Thus, beside the control of parasitemia by the immune system of the host, cell density is also regulated by the parasite itself.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form

et al. 2005

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African trypanosomes produce some prostanoids, especially PGD 2 , PGE 2 and PGF 2a (Kubata et al. 2000, J. Exp. Med. 192: 1327-1338, probably to interfere with the host's physiological response. However, addition of prostaglandin D 2 (but not PGE 2 or PGF 2a ) to cultured bloodstream form trypanosomes led also to a significant inhibition of cell growth. Based on morphological alterations and specific staining methods using vital dyes, necrosis and autophagy were excluded. Here, we report that in bloodstream form trypanosomes PGD 2 induces an apoptosis-like programmed cell death, which includes maintenance of plasma membrane integrity, phosphatidylserine exposure, loss of mitochondrial membrane potential, nuclear chromatin condensation and DNA degradation. The use of caspase inhibitors cannot prevent the cell death, indicating that the process is caspase-independent. Based on these results, we suggest that PGD 2 -induced programmed cell death is part of the population density regulation as observed in infected animals.

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Regulation of Parasitaemia in Mice Infected with Trypanosoma brucei

Cited by 47 publications

References 54 publications

Deletion of a novel protein kinase with PX and FYVE‐related domains increases the rate of differentiation of Trypanosoma brucei

Deletion of a novel protein kinase with PX and FYVE‐related domains increases the rate of differentiation of Trypanosoma brucei

The Role of B-cells and IgM Antibodies in Parasitemia, Anemia, and VSG Switching in Trypanosoma brucei–Infected Mice

Prostaglandin D2 induces programmed cell death in Trypanosoma brucei bloodstream form

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