Alpha-tocopherol transfer protein gene disruption confers resistance to protozoan infections

Abstract number: P991

Herbas M., Xuan X., Arai H., Suzuki H.

Objective: The nutritional status of the host influences susceptibility or resistance against protozoan infection. Micronutrient deficiency, such as vitamin E might play a protective role against infection. Mice deficient in alpha-tocopherol transfer protein (alpha-TTP), with undetectable levels of vitamin E in circulation, were used as a model to analyze the effect of vitamin E deficiency on the outcome of protozoan infections, in order to propose a new strategy for the prevention and control of protozoan infections by modification of the nutritional status of the host.

Methods: alpha-TTP knockout mice were infected with Plasmodium berghei or Trypanosoma congolense at lethal doses, and their survival rates and parasitaemia were recorded. DNA damage of parasites was evaluated by means of comet assay and anti-8-OHdG test and antioxidant defence system in parasites was examined by monitoring the mRNA expression of antioxidative stress enzymes by real time quantitative PCR.

Results: alpha-TTP knockout mice infected with P. berghei or T. congolense survived significantly longer than the wild type mice (p < 0.05). The percentage of parasitaemia in alpha-TTP knockout mice infected with P. berghei, remained at very low levels during the acute phase of infection. Whereas, parasite density in the knockout mice infected with T. congolense remained at very low levels compared to wild type mice (p < 0.01). Comet assay revealed clear comet tails in the parasites infecting alpha-TTP knockout mice, such tails were not observed in parasites infecting the wild type mice. In addition, anti-8-OHdG test revealed a positive reaction in the parasites infecting the alpha-TTP knockout mice. Furthermore, mRNA expression of antioxidative stress enzymes from parasites infecting alpha-TTP knockout mice were significantly up-regulated after infection (p < 0.05). Expression levels were significantly higher in parasites infecting knockout mice as compared to parasites infecting wild type mice (p < 0.05).

Conclusion: Inhibition of alpha-TTP confers resistance to the development of protozoan infections, and this resistance is induced by oxidative damage of the parasites due to vitamin E deficiency in the circulation of the host. Inhibition of alpha-TTP activity might be an interesting alternative for the control, prevention and treatment of protozoan infections.