The obligate intracellular parasite Toxoplasma gondii is a major opportunistic infection of AIDS patients. Toxoplasma also causes devastating disease to fetuses and other immunocompromised patients. While much work has focused on identifying and characterizing Toxoplasma proteins and pathways important for growth and virulence of this intracellular pathogen, less is known about which host cell processes are rate-limiting for parasite growth. Identification of these host cell processes is important because if we can inhibit them from functioning, then we can block parasite growth and disease. Modulation of host cell transcription is a common mechanism that pathogens use to alter the host cell's environment to become permissive for pathogen growth. Our previous work demonstrated that Toxoplasma rapidly and specifically activated a host cell transcription factor named Hypoxia Inducible Factor 1 (HIF1). HIF1 is heterodimeric transcription factor composed of alpha and beta subunits that regulates transcription by either directly binding DNA or by repressing the activity of a second transcription factor, c-myc. Significantly, we find that HIF1 is necessary for Toxoplasma growth at physiological oxygen levels even though this transcription factor is dispensable for host cell growth and survival. These data indicate that HIF1 regulates the expression of host cell genes that function in pathways necessary for Toxoplasma growth. In addition, they are the first to demonstrate that a host cell transcription factor is required for Toxoplasma to grow within its host cell. The goals of this proposal are to elucidate how Toxoplasma activates HIF1 and to identify the HIF1-regulated pathways necessary for parasite growth. Specifically, Specific Aim 1 will identify the step in the HIF1 activation pathway that is modulated by infection.
Specific Aim 2 will examine whether Toxoplasma requires HIF1 to regulate transcription by directly binding DNA and by repressing c-myc.
In Specific Aim 3, we will identify the HIF1 regulated genes and pathways that are important for Toxoplasma growth. These studies are likely to provide important information regarding the interaction between Toxoplasma and its host cell. In addition, they will provide important information to develop new drugs to treat toxoplasmosis. ? ? ?
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