Role of Activins in Hepcidin Regulation during Malaria
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Role of Activins in Hepcidin Regulation during Malaria. / Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R; Fyfe, Alex J; Biswas, Sumi; Hodgson, Susanne H; Llewellyn, David; Choudhary, Prateek; Draper, Simon J; Duffy, Patrick; Drakesmith, Hal.
In: Infection and Immunity, Vol. 85, No. 12, e00191-17, 2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Role of Activins in Hepcidin Regulation during Malaria
AU - Spottiswoode, Natasha
AU - Armitage, Andrew E
AU - Williams, Andrew R
AU - Fyfe, Alex J
AU - Biswas, Sumi
AU - Hodgson, Susanne H
AU - Llewellyn, David
AU - Choudhary, Prateek
AU - Draper, Simon J
AU - Duffy, Patrick
AU - Drakesmith, Hal
N1 - Copyright © 2017 Spottiswoode et al.
PY - 2017
Y1 - 2017
N2 - Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway, and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naïve volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins are unlikely to stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signalling pathway is perturbed in malaria infection, but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting.
AB - Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway, and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naïve volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins are unlikely to stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signalling pathway is perturbed in malaria infection, but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting.
KW - Journal Article
U2 - 10.1128/IAI.00191-17
DO - 10.1128/IAI.00191-17
M3 - Journal article
C2 - 28893916
VL - 85
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 12
M1 - e00191-17
ER -
ID: 184767065