Alpha-tocopherol transfer protein disruption confers resistance to malarial infection in mice.
BACKGROUND
Various factors impact the severity of malaria, including the nutritional status of the host. Vitamin E, an intra and extracellular anti-oxidant, is one such nutrient whose absence was shown previously to negatively affect Plasmodium development. However, mechanisms of this Plasmodium inhibition, in addition to means by which to exploit this finding as a therapeutic strategy, remain unclear.


METHODS
alpha-TTP knockout mice were infected with Plasmodium berghei NK65 or Plasmodium yoelii XL-17, parasitaemia, survival rate were monitored. In one part of the experiments mice were fed with a supplemented diet of vitamin E and then infected. In addition, parasite DNA damage was monitored by means of comet assay and 8-OHdG test. Moreover, infected mice were treated with chloroquine and parasitaemia and survival rate were monitored.


RESULTS
Inhibition of alpha-tocopherol transfer protein (alpha-TTP), a determinant of vitamin E concentration in circulation, confers resistance to malarial infection as a result of oxidative damage to the parasites. Furthermore, in combination with the anti-malarial drug chloroquine results were even more dramatic.


CONCLUSIONS
Considering that these knockout mice lack observable negative impacts typical of vitamin E deficiency, these results suggest that inhibition of alpha-TTP activity in the liver may be a useful strategy in the prevention and treatment of malaria infection. Moreover, a combined strategy of alpha-TTP inhibition and chloroquine treatment might be effective against drug resistant parasites.
Herbas
Maria S
MS
Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Nishi 2-13, Inada, Obihiro, 080-8555 Japan.
Ueta
Yoshiko Y
YY
Ichikawa
Chie
C
Chiba
Mayumi
M
Ishibashi
Kana
K
Shichiri
Mototada
M
Fukumoto
Shinya
S
Yokoyama
Naoaki
N
Takeya
Motohiro
M
Xuan
Xuenan
X
Arai
Hiroyuki
H
Suzuki
Hiroshi
H
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002738:Chloroquine / Q000627:therapeutic use; D007113:Immunity, Innate; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D010967:Plasmodium yoelii / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D015996:Survival Rate; D014810:Vitamin E / Q000008:administration & dosage / Q000378:metabolism; D014811:Vitamin E Deficiency; D014815:Vitamins / Q000008:administration & dosage / Q000378:metabolism
D000962:Antimalarials; D002352:Carrier Proteins; D014815:Vitamins; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D002738:Chloroquine
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