Manipulation of host cell acetylome in AIDS opportunistic infection

描述(申请人提供)：机会性病原体仍然是艾滋病毒/艾滋病患者的一个严重问题，降低了生活质量，并经常造成危及生命的急性感染。弓形虫是一种专性的细胞内原生动物寄生虫(尖端复合门)，已永久感染世界人口的三分之一。虽然通常认为在免疫能力强的人中是良性的，但弓形虫在艾滋病患者中复发成为活动性感染是臭名昭著的。抗叶酸的一线治疗显示出明显的 不良反应和过敏患者无法忍受的磺胺类成分。因此，迫切需要开发更安全和更有效的疗法来治疗艾滋病-弓形虫病。像其他细胞内艾滋病机会性感染一样，弓形虫从根本上改变了宿主细胞环境，以适应寄生虫的需要。一种创新的治疗策略是干扰 对宿主细胞的修饰，从而使其不适合寄生虫的复制和发展。不幸的是，我们对宿主-病原体相互作用的了解不足阻碍了新药的开发。最近发现，细胞内的病毒和细菌病原体改变宿主细胞蛋白质的乙酰化，操纵一个主要的细胞信号网络，有利于寄生虫的生存。我们假设弓形虫也操纵宿主细胞的乙酰化，并提出了支持这一观点的证据。我们发现弓形虫感染会导致调节蛋白质乙酰化的酶的转录水平发生改变。此外，抗乙酰赖氨酸免疫印迹揭示了感染宿主细胞中蛋白质乙酰化水平的整体变化。因此，我们建议确定宿主细胞的蛋白质 在弓形虫感染的背景下修饰毒力并发展到潜伏期，并识别与感染相关的特定赖氨酸(去乙酰化)酶。鉴于在真核细胞中发现的赖氨酸乙酰化的范围以及多种细胞内病原体扰乱乙酰化动力学的共同主题，我们的发现有望对其他医学相关感染产生深远影响，包括艾滋病毒本身和其他艾滋病机会主义病原体，如隐孢子虫。

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.