STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

Thawani, Neeta; Tam, Mifong; Stevenson, Mary M.

doi:10.3324/haematol.13422

Cited by 33 publications

(27 citation statements)

References 50 publications

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“…Furthermore, it is accepted that severe anemia, another important cause of disease severity common to P. falciparum and Plasmodium vivax malaria, does not occur as a result of destruction of iRBCs per se, because for every iRBC destroyed during malaria, ∼32 non-iRBCs are removed from the circulation (39). Cytokines such as TNF-α and IFN-γ suppress hematopoiesis and enhance uptake of noninfected erythrocytes (40), contributing to anemia (41)(42)(43). Thus, irrespective of the underlying events driving the pathogenesis of malaria, there is strong evidence for the direct or indirect implications of proinflammatory cytokines (34,35).…”

Section: Discussionmentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

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

106

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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Section: Discussionmentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

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

106

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“…20 Thawani and colleagues exploited STAT6-deficient mice to investigate malarial anemia in the P. chabaudi AS animal model. 17 These malaria-infected mice had an earlier and higher reticulocytosis despite having a higher peak parasitemia and a similar degree of anemia when compared to infected control mice. Exogenous erythropoietin treatment enhanced this reticulocytosis.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…Thawani and colleagues provide evidence to suggest that a deficiency in STAT6 restricted the diversion of transferrin receptor 1 from erythroid to non-erythroid cells, thus maintaining iron availability to erythropoietin-responsive erythroid precursors. 17 In P. chabaudiinfected mice, they also found increased proliferation of erythropoietin-treated splenocytes in STAT6-deficient animals when compared to in wild-type controls. The question they then posed was whether STAT6 played a role in IFN-γ production by natural killer and natural killer T cells in malarial anemia.…”

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confidence: 99%

“…The paper by Thawani et al, in this issue of the journal, describes the STAT6-mediated suppression of erythropoiesis in an experimental animal model of malarial anemia. 17 STAT6 is a member of the signal transducer and activator of transcription (STAT) family of proteins of which there are six other members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b) 18 . Studies using STAT6-deficient mice have revealed the key role that this protein plays in IL-4 and IL-13 signaling and in Th2 polarization of the immune system.…”

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confidence: 99%

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Malarial anemia and STAT6

Robson¹,

Weatherall²

2009

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nmimicking what is seen in other acute infections.There is still much to understand about the mechanisms of the ineffective marrow response. It is possible that the suppression in the bone marrow is a consequence of the high levels of TNF-α that result from a malaria infection 8 . This cytokine is implicated in the anemia of chronic infection. TNF-α suppresses the growth of erythroid progenitor cells in human bone marrow cultures, though this effect lessens as the cells differentiate. However, TNF-α stimulates fibroblasts to secrete hematopoietic growth factors in vitro. The pigment resulting from the malaria parasite is ingested by resident macrophages in the spleen and marrow, resulting in the production of TNF-α at the site of erythropoiesis. Work in mice supports a role for TNF-α in the dyserythropoietic changes resulting from malaria infection. Other cytokines, such as interleukin (IL)-10, may contribute to dyserythropoiesis. IL-10 is an inhibitory cytokine that acts in opposition to TNF-α. It was shown in a study of African children with severe malarial anemia that the TNF-α:IL-10 ratio was high in plasma, suggesting that low levels of IL-10 contribute to the TNF-α suppression of erythropoiesis.15 Another cytokine, IL-12, protects against severe anemia in a mouse model. 16The parasite by-product of hemoglobin digestion, hemozoin also plays a role in the suppression of erythropoiesis.What other factors may be involved in modulating erythropoiesis in malaria? The paper by Thawani et al., in this issue of the journal, describes the STAT6-mediated suppression of erythropoiesis in an experimental animal model of malarial anemia.17 STAT6 is a member of the signal transducer and activator of transcription (STAT) family of proteins of which there are six other members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b) 18. Studies using STAT6-deficient mice have revealed the key role that this protein plays in IL-4 and IL-13 signaling and in Th2 polarization of the immune system. STAT6 is ubiquitously expressed.The STAT6 signaling cascade is activated when IL-4 or IL-13 engage with their corresponding receptor (Figure 1). The major receptor for IL-4 consists of IL-4R· and the common γ chain (γc). 19 Signaling is initiated by the binding of IL-4 to IL-4Rα which then dimerises with γc ( Figure 1). The type II IL-4 receptor is composed of IL-4Rα and IL-13Rα1 chains and can, consequently, transmit signals from IL-4 and IL-13. Once the particular cytokine is engaged, this leads to the phosphorylation of a specific Janus kinase (JAK) and the consequent phosphorylation of three tyrosine residues on IL-4Rα which then provides the necessary docking site for STAT6 (Figure 1). JAK then phosphorylates STAT6 which in turn dimerizes, and is translocated to the nucleus where it binds to DNA regulating the transcription of certain genes ( Figure 1). STAT6 can also be activated by other pathways 18 . STAT6 binds to a highly conserved DNA sequence motif; the consensus is TTC(N)2-4GAA. This was...

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“…Studies in inbred and recombinant congenic mouse strains have mapped several major Chabaudi resistance loci (Char1-Char9) that control the extent of P. chabaudi replication in the blood at the peak of infection (peak parasitemia) and affect overall survival (reviewed in Fortin et al 7 and Hernandez-Valladares et al 8 ). Most of these quantitative trait loci (QTLs) are defined by large chromosomal regions (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and account for only a fraction of the phenotypic variance, making it difficult to identify the gene(s) involved. We have used a set of 36 AcB/BcA recombinant congenic strains, derived from susceptible A/J and resistant C57BL/6J (B6) progenitors and generated by two backcrosses followed by inbreeding, to dissect the complex genetic control of differential susceptibility to P.chabaudi in these two strains.…”

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confidence: 99%

Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

Min‐Oo¹,

Willemetz²,

Tam³

et al. 2009

Genes Immun

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Resistance to blood-stage malaria in AcB55 and AcB61 is caused by a loss of function mutation in pyruvate kinase (Pklr I90N ). Likewise, pyruvate kinase (PK) deficiency in humans is protective against Plasmodium replication in vitro. We identified a third AcB strain, AcB62 that also carries the Pklr I90N mutation. However, AcB62 mice were susceptible to P.chabaudi infection and showed high levels of parasite replication (54-62% peak parasitemia). AcB62 mice showed the hallmarks of PK deficiencyassociated anemia similar to AcB55/61 with reticulocytosis, splenic red pulp expansion, tissue iron overload, and increased expression of iron metabolism proteins. This suggests that malaria susceptibility in AcB62 is not because of absence of PK deficiency-associated pathophysiology. To map novel genetic factors affecting malaria susceptibility in AcB62, we generated an informative F2 population using AcB62 (Pklr I90N ) and CBA-Pk slc (Pklr G338D ) as progenitors and identified a novel locus on chromosome 9 (Char10; LOD ¼ 7.24) that controls peak parasitemia. A weaker linkage to the Pklr region of chromosome 3 (LOD ¼ 3.7) was also detected, a finding that may reflect the segregation of the two defective Pklr alleles. AcB62 alleles at both loci are associated with higher peak parasitemia. These results identify Char10 as a novel locus modulating severity of malaria in the context of PK deficiency.

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STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

Cited by 33 publications

References 50 publications

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Malarial anemia and STAT6

Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9

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