期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7778-E7787
DOI：10.1073/pnas.1608221113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe parasite Trypanosoma brucei causes African sleeping sickness. This disease, which lacks effective treatments, affects millions of humans and livestock in sub-Saharan Africa. This paper reveals a mechanism by which the parasite can evade our immune response. Indolepyruvate is a metabolite produced by the parasite and it manipulates the immune cells, called macrophages, preventing them from becoming fully active. The selective advantage for the parasite of excretion of indolepyruvate is possible modulation of host inflammatory responses to prolong host survival, thereby potentiating transmission of the parasite to the tsetse fly vector and ensuring completion of the life cycle. This discovery could lead to new drug targets and better treatments. The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stage-dependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1 (HIF-1). The reduction in HIF-1 levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1{beta}. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.
