Grants and Contracts Details
The protozoan parasite Toxoplasma gondii is an important opportunistic infection causing life threatening disease in patients with HIV-AIDS and other immune compromising conditions. The high seroprevalence of the T. gondii worldwide but low incidence of symptomatic disease reflects the fact that the acute phase of infection is effectively handled by the immune response. Unfortunately a sterile cure is not achieved. Rather the parasite establishes a life-long chronic infections mediated by tissue cysts typically formed in the brain and muscle. The tissue cyst is protected by a heavily glycosylated cyst wall. Despite the importance of glycosylation, little is known about these pathways in the parasite. Toward this end we propose to perform a comprehensive bioinformatic analysis of the glycosyltransferase repertoire in the parasite genome. Al alternative means of glycosylation could be the hijacking of host activities. In the course of examining lectin reactivity to parasite glycans in tachyzoites and tissue cysts we have found evidence for considerable diversity in the glycan repertoire. Interestingly, despite lacking the enzymatic machinery for the generation of complex N-glycans and sialylation, we find evidence for these modifications particularly in in vivo derived tissue cysts. The apparent absence of the activities in the parasite genome suggests involvement of the infected host cell. We explore and test the novel hypothesis that the delivery of host activities to the parasitophorous vacuole is mediated by transient fusion of the PVM-associated ER that is accelerated in the course of cyst formation. We further investigate whether the parasite hijacks elements of the Golgi apparatus to access Golgi resident activities. Finally we directly test the contribution of selected host enzymes by the use of specific host cell mutants and RNAi mediated knockdown of activities. We believe that hijacking of the host glycosylation machinery may play a critical role in immune evasion by in effect ‘sugar coating” potentially immunogenic antigens and presenting determinants that are viewed as immunological self.
|Effective start/end date||1/18/13 → 12/31/15|
- National Institute of Allergy and Infectious Diseases: $408,375.00
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