Alpha-tocopherol transfer protein disruption confers resistance to malarial infection in mice

Abstract

BackgroundVarious 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.Methodsα-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.ResultsInhibition of α-tocopherol transfer protein (α-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.ConclusionConsidering that these knockout mice lack observable negative impacts typical of vitamin E deficiency, these results suggest that inhibition of α-TTP activity in the liver may be a useful strategy in the prevention and treatment of malaria infection. Moreover, a combined strategy of α-TTP inhibition and chloroquine treatment might be effective against drug resistant parasites.

Probucol-Induced α-Tocopherol Deficiency Protects Mice against Malaria Infection

“…After probucol treatment for 2 weeks, a subgroup of the treated mice was fed with a standard diet for 2 weeks. Blood samples were obtained under anesthesia with diethyl ether (Wako; Tokyo, Japan) by cardiac puncture using sodium citrate (Wako; Tokyo, Japan) as an anticoagulant, and then blood samples were centrifuged at 5000 rpm for 5 min at 4°C to remove the plasma and buffy coat [ 22 ].…”

“…Recently, we have reported that α-tocopherol transfer protein knockout (α-ttp Δ ) mice showing undetectable plasma concentrations of α-tocopherol, the most biologically active form of vitamin E, were resistant against malaria and cerebral malaria [ 21 ]. This resistance was attributed to the parasite DNA damage derived from the high oxidative stress due to α-tocopherol deficiency [ 22 ]. We have also demonstrated that this protective effect can be reversed by feeding α-ttp Δ mice with α-tocopherol-supplemented diets [ 21 , 22 ].…”

“…This resistance was attributed to the parasite DNA damage derived from the high oxidative stress due to α-tocopherol deficiency [ 22 ]. We have also demonstrated that this protective effect can be reversed by feeding α-ttp Δ mice with α-tocopherol-supplemented diets [ 21 , 22 ].…”

Multivariable analysis of host amino acids in plasma and liver during infection of malaria parasite Plasmodium yoelii

“…Donor BALB/c mice were intraperitoneally injected with 1×10 6 erythrocytes infected with P. yoelii 17XL strain [19,20]. Parasitaemia was monitored by counting the number of parasite-infected erythrocytes per 1,000 erythrocytes by microscopic examination of Giemsa-stained, thin (tail) blood smears.…”

New Insights into Malaria Prophylaxis

“…[22][23][24] Mice which lack the α-TTP liver cytosolic protein and which have very little vitamin E in circulation are highly resistant against malaria. 25 The consumption of foods rich in vitamin E like peanut butter or moringa has probably to be reduced to avoid malaria infections. The same probably applies to vegetable oils rich in vitamin E or even vegetable gelatin capsules where at the Worcester Polytechnic Institute it was found that these food components significantly decrease the recovery of artemisinin, a strong oxidant, from the intestinal liquid phase, but not those of flavonoids.…”