Role of iron homeostasis in trypanosomiasis-associated anemia

Stijlemans, Benoı̂t; Vankrunkelsven, Ann; Brys, Lea; Magez, Stefan; Baetseĺier, Patrick De

doi:10.1016/j.imbio.2008.07.023

Cited by 67 publications

(80 citation statements)

References 47 publications

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“…However, the genes for transferrin receptors 1 and 2 (Tf-R1 and Tf-R2), which are major determinants maintaining iron homeostasis, were both significantly upregulated in strain 247-infected mice compared to strain 927-infected mice. Of these two genes, Tf-R1 was highly significantly differentially expressed (3.0-fold change) at day 10, in agreement with previous data on the upregulation of this gene in the acute stage of infection (77). In the latter study and others (76), the acute stage of infection was associated with type 1 cytokines, but in the present study, the picture is less clear, as the anemic mice expressed both a type 2 (IL-10-dominated response) and a type 1 cytokine (IFN-␥).…”

Section: Vol 78 2010 Strain-specific Pathogenesis In Trypanosome Insupporting

confidence: 91%

“…The genes associated with a reduced erythropoietic response in C57BL/6 mice in response to T. congolense infection, namely, those for structural proteins (spectrin and glycophorin) and transcription factors (Lmo2, Zfpm1, Klf1, and Tcfe2a), were also expressed at lower levels in the spleens of BALB/c mice infected with strain 927-infected compared with strain 247-infected BALB/c mice (all significant at an FDR of Ͻ5). Iron homeostasis has also been suggested to play a role in trypanosome-induced anemia (59,77), and we found some evidence for this in our study. Most of the genes previously identified were either not differentially expressed relative to control mice (hepcidin, ferritin, Dmt-1, Fpn-1, Fhc, CD16, CD91) or not differentially expressed between infections with the two trypanosome strains (Hmox-1, ceruloplasmin, CD36, and transferrin, all downregulated to similar levels in both infections).…”

Section: Vol 78 2010 Strain-specific Pathogenesis In Trypanosome Insupporting

confidence: 80%

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Role for Parasite Genetic Diversity in Differential Host Responses toTrypanosoma bruceiInfection

et al. 2010

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The postgenomic era has revolutionized approaches to defining host-pathogen interactions and the investigation of the influence of genetic variation in either protagonist upon infection outcome. We analyzed pathology induced by infection with two genetically distinct Trypanosoma brucei strains and found that pathogenesis is partly strain specific, involving distinct host mechanisms. Infections of BALB/c mice with one strain (927) resulted in more severe anemia and greater erythropoietin production compared to infections with the second strain (247), which, contrastingly, produced greater splenomegaly and reticulocytosis. Plasma interleukin-10 (IL-10) and gamma interferon levels were significantly higher in strain 927-infected mice, whereas IL-12 was higher in strain 247-infected mice. To define mechanisms underlying these differences, expression microarray analysis of host genes in the spleen at day 10 postinfection was undertaken. Rank product analysis (RPA) showed that 40% of the significantly differentially expressed genes were specific to infection with one or the other trypanosome strain. RPA and pathway analysis identified LXR/RXR signaling, IL-10 signaling, and alternative macrophage activation as the most significantly differentially activated host processes. These data suggest that innate immune response modulation is a key determinant in trypanosome infections, the pattern of which can vary, dependent upon the trypanosome strain. This strongly suggests that a parasite genetic component is responsible for causing disease in the host. Our understanding of trypanosome infections is largely based on studies involving single parasite strains, and our results suggest that an integrated host-parasite approach is required for future studies on trypanosome pathogenesis. Furthermore, it is necessary to incorporate parasite variation into both experimental systems and models of pathogenesis.

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Section: Vol 78 2010 Strain-specific Pathogenesis In Trypanosome Insupporting

confidence: 91%

Section: Vol 78 2010 Strain-specific Pathogenesis In Trypanosome Insupporting

confidence: 80%

Role for Parasite Genetic Diversity in Differential Host Responses toTrypanosoma bruceiInfection

et al. 2010

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“…However, most studies on transferrin uptake in T. brucei have not taken into account that in chronic trypanosomiasis, especially in cattle, there is profound anaemia (d 'Ieteren et al 1998 ;Naessens, 2006) in which host transferrin levels, particularly holotransferrin, are decreased. In such a situation, antibodies against the ESAG6/7 transferrin receptor may have a far more significant effect on trypanosomal iron uptake since they are competing with decreased levels of transferrin, particularly if the expressed transferrin receptor has a low affinity for the transferrin of that host (Stijlemans et al 2008). It is possible that this chronic and progressive host anaemia is one reason why bloodstream-form T. brucei have evolved to require relatively little iron (Steverding, 1998).…”

Section: Iron Transport In Trypanosomatidsmentioning

confidence: 99%

Iron metabolism in trypanosomatids, and its crucial role in infection

Taylor

Kelly

2010

Parasitology

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Iron is almost ubiquitous in living organisms due to the utility of its redox chemistry. It is also dangerous as it can catalyse the formation of reactive free radicals -a classical double-edged sword. In this review, we examine the uptake and usage of iron by trypanosomatids and discuss how modulation of host iron metabolism plays an important role in the protective response. Trypanosomatids require iron for crucial processes including DNA replication, antioxidant defence, mitochondrial respiration, synthesis of the modified base J and, in African trypanosomes, the alternative oxidase. The source of iron varies between species. Bloodstream-form African trypanosomes acquire iron from their host by uptake of transferrin, and Leishmania amazonensis expresses a ZIP family cation transporter in the plasma membrane. In other trypanosomatids, iron uptake has been poorly characterized. Iron-withholding responses by the host can be a major determinant of disease outcome. Their role in trypanosomatid infections is becoming apparent. For example, the cytosolic sequestration properties of NRAMP1, confer resistance against leishmaniasis. Conversely, cytoplasmic sequestration of iron may be favourable rather than detrimental to Trypanosoma cruzi. The central role of iron in both parasite metabolism and the host response is attracting interest as a possible point of therapeutic intervention.

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“…Near the middle part of the gene is a hypervariable region of approximately 32 nucleotides [Pays, 2006]. Affinity binding of TbTFR for TF is important when the host begins to make a significant Ab response against invariant regions of the receptor that could interfere with TF uptake [Borst, 1991;Salmon et al, 1994;Steverding et al, 1995;Steverding, 2003;Steverding, 2006;Stijlemans et al, 2008]. In some cases, these Abs compete with TF for the receptor binding site, and only a high-affinity receptor could maintain the required iron level for trypanosome replication [Bitter et al, 1998].…”

Section: T Brucei Transferrin Receptor (Tbtfr)mentioning

confidence: 99%