Toxoplasma gondii is a widespread parasite of domestic and wild animals that also commonly infects humans, where it is an important cause of disease in immunocompromised individuals. T. gondii is also a model for many biological features are conserved in other less-easily studied apicomplexan parasites such as Cryptosporidium and Plasmodium (malaria). For example, this group of parasites shares common pathways for protein secretion, motility, and host cell invasion: adaptations that are responsible for the success of these intracellular parasites. The long-term goal of our studies is to elucidate the molecular mechanisms that regulate these conserved pathways in apicomplexan parasites and to define how these adaptations lead to intracellular parasitism. Previous studies have demonstrated the role of actin-based motility in cell invasion, and shown that this process facilitates tissue migration and contributes to pathogenesis. Motility and cell invasion also require calcium-mediated secretion of micronemal proteins, which bind to specific receptors on the host cell or substratum, thus providing traction. The cytoplasmic domains of micronemal proteins link to the motor complex within the parasite, thus bridging substrate attachment with force generation. In the proposed studies, we will define the molecular mechanisms that control three important steps in the function of microneme proteins including, calcium-mediated release, translocation via the motor complex, and proteolytic processing. Importantly, these molecular components and signaling pathways are not found in the host cell, they have been shown to be essential in the parasite using pharmacological and/or genetic analyses, and they are conserved among apicomplexan parasites. Elucidation of the molecular mechanisms that control these events will lead to an increased understanding of unique adaptations that are essential for survival of apicomplexan parasites. They may also lead to improved therapeutic interventions to combat these important pathogens.
Our studies are designed to elucidate the molecular mechanisms that control protein secretion and motility in apicomplexan parasites. The proposed studies will be conducted using T. gondii, which is an important opportunistic pathogen and NIAID category B Biodefense agent. T. gondii is also a laboratory model for other less easily studied parasites such as Plasmodium and Cryptosporidium, which share these same biological pathways. Because these pathways are essential and unique to these parasites, defining their molecular components and regulatory features may enable future development of new treatments for parasitic diseases.
|Lorenzi, Hernan; Khan, Asis; Behnke, Michael S et al. (2016) Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes. Nat Commun 7:10147|
|Long, Shaojun; Wang, Qiuling; Sibley, L David (2016) Analysis of Noncanonical Calcium-Dependent Protein Kinases in Toxoplasma gondii by Targeted Gene Deletion Using CRISPR/Cas9. Infect Immun 84:1262-73|
|Behnke, Michael S; Dubey, J P; Sibley, L David (2016) Genetic Mapping of Pathogenesis Determinants in Toxoplasma gondii. Annu Rev Microbiol 70:63-81|
|Brown, Kevin M; Lourido, Sebastian; Sibley, L David (2016) Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii. J Biol Chem 291:9554-65|
|Hui, Raymond; El Bakkouri, Majida; Sibley, L David (2015) Designing selective inhibitors for calcium-dependent protein kinases in apicomplexans. Trends Pharmacol Sci 36:452-60|
|Kuhlenschmidt, Theresa B; Rutaganira, Florentine U; Long, Shaojun et al. (2015) Inhibition of Calcium-Dependent Protein Kinase 1 (CDPK1) In Vitro by Pyrazolopyrimidine Derivatives Does Not Correlate with Sensitivity of Cryptosporidium parvum Growth in Cell Culture. Antimicrob Agents Chemother 60:570-9|
|Drewry, Lisa L; Sibley, L David (2015) Toxoplasma Actin Is Required for Efficient Host Cell Invasion. MBio 6:e00557|
|Shen, Bang; Buguliskis, Jeffrey S; Lee, Tobie D et al. (2014) Functional analysis of rhomboid proteases during Toxoplasma invasion. MBio 5:e01795-14|
|Shen, Bang; Sibley, L David (2014) Toxoplasma aldolase is required for metabolism but dispensable for host-cell invasion. Proc Natl Acad Sci U S A 111:3567-72|
|Alaganan, Aditi; Fentress, Sarah J; Tang, Keliang et al. (2014) Toxoplasma GRA7 effector increases turnover of immunity-related GTPases and contributes to acute virulence in the mouse. Proc Natl Acad Sci U S A 111:1126-31|
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