Manipulation of host cell acetylome in AIDS opportunistic infection

描述（由申请人提供）：机会致病菌仍然是艾滋病毒/艾滋病患者的一个重要问题，降低了生活质量，并经常造成危及生命的急性感染。刚地弓形虫是一种专性细胞内原生动物寄生虫（顶复虫门），它已经永久感染了世界上多达三分之一的人口。弓形虫在免疫能力强的个体中通常被认为是良性的，但它在艾滋病患者中以复发为活动性感染而臭名昭著。抗叶酸药物的一线治疗效果显著

DESCRIPTION (provided by applicant): Opportunistic pathogens remain a significant problem in HIV/AIDS patients, decreasing the quality of life and often posing life-threatening acute infection. Toxoplasma gondii is an obligate intracellular protozoan parasite (phylum Apicomplexa) that has permanently infected up to 1/3 of the world's population. While generally considered benign in immune-competent individuals, Toxoplasma is notorious for recrudescing into active infection in AIDS patients. The frontline treatment of anti-folates exhibits pronounced adverse effects and a sulfa component that allergenic patients cannot tolerate. Thus, an urgent need exists to develop safer and more effective therapies to treat AIDS-toxoplasmosis. Like other intracellular AIDS opportunistic infections, Toxoplasma radically alters its host cell environment to suit the parasite's needs. An innovative treatment strategy is to interfere with the modifications made to the host cell, thereby making it inhospitable for parasite replication and development. Unfortunately, a deficiency in our understanding of host-pathogen interactions has stymied the development of new drugs. It has recently been found that intracellular viral and bacterial pathogens alter acetylation of host cell proteins, manipulating a major cellular signalin network in favor of parasite survival. We hypothesize that Toxoplasma also manipulates host cell acetylation and present evidence in support of this idea. We show that Toxoplasma infection induces alterations in the transcript levels of enzymes modulating protein acetylation. Furthermore, immunoblotting with anti-acetyl- lysine reveals global changes in protein acetylation levels in infected host cells. We therefore propose to determine the host cell proteins modified by Toxoplasma infection in the context of virulence and development into its latent stage, and identify specific lysine (de)acetylation enzymes that are relevant to infection. Given the scope of lysine acetylation found in eukaryotic cells and the common theme of multiple intracellular pathogens disrupting acetylation dynamics, our findings promise to have far-reaching impact on other medically relevant infections, including HIV itself and other AIDS opportunist pathogens such as Cryptosporidium.