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Manipulation of Host Cell Acetylome in AIDS Opportunistic Infection

Sullivan Jr, William
Indiana University-Purdue University Indianapolis
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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 pronouncedadverse 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 themodifications 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 proteinsmodified 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.
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PUBLIC HEALTH RELEVANCE: Toxoplasma is an intracellular parasite that persists as an opportunistic latent cyst, which is frequently reactivated in HIV/AIDS patients causing serious and potentially fatal pathologies. Despite administration of HAART, the mortality rate of patients suffering from HIV-associated CNS disease, such as cerebral toxoplasmosis, remains high. Our proposal aims to pioneer a new area of study that examines the changes in host cell protein modification during Toxoplasma infection, and the results promise to have far-reaching impact on other medically relevant infections, including HIV itself and other AIDS opportunist pathogens such as Cryptosporidium.
Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
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Bacterial Pathogens