Toxoplasma gondii is a common parasitic infection of humans that causes opportunistic disease in immunocompromised patients, including those with AIDS or those undergoing chemotherapy for cancer or organ transplant. The symptoms of infection vary considerably, ranging from subclinical to severe, although the factors that control these disparate outcomes are poorly understood. One component that likely contributes to disease severity is the genetic makeup of the parasite. However, little is known about the specific parasite genes that are responsible for influencing disease severity. Our previous studies have shown that T. gondii has a highly unusual genetic makeup consisting of three clonal lineages that are wide spread in North America and Europe. These three strain types differ substantially in the immune responses they evoke and the severity of infections that they cause. The proposed studies will investigate the molecular basis of acute virulence in Toxoplasma gondii using forward and reverse genetics to identify genes important for pathogenesis. We will explore the role of secretory kinases, recently implicated as major virulence determinants of T. gondii, and characterize their cellular and biochemical mechanisms of action. Additional genetic crosses between different parasite genotypes will be undertaken to map genes that regulate differences in pathogenesis, including genes that control tissue migration, induction of immune responses, and acute virulence. Finally, we will identify genes that contribute to pathogenesis of newly described T. gondii lineages from other geographic regions. Forward and reverse genetic analyses will be used to map genes and determine the molecular basis of virulence in these newly identified parasite lineages. These studies will provide important fundamental knowledge about the identify and mechanisms of action of virulence determinants in T. gondii that contribute to human disease.
Toxoplasma gondii is a widespread parasitic infection that can cause severe disease in immunocompromised patients. Our studies seek to define the factors that contribute to the severity of disease caused by this parasite. By understanding the virulence determinants of the parasite that enable it to cause harm, it may be possible to develop new therapeutic approaches to combat human infection. The findings are highly relevant to the pathology of toxoplasmosis in immunocompromised patient, including individuals with AIDS.
|Olias, Philipp; Etheridge, Ronald D; Zhang, Yong et al. (2016) Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-Î³-Dependent Gene Expression. Cell Host Microbe 20:72-82|
|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|
|Shaik, Jahangheer S; Khan, Asis; Beverley, Stephen M et al. (2015) REDHORSE-REcombination and Double crossover detection in Haploid Organisms using next-geneRation SEquencing data. BMC Genomics 16:133|
|Behnke, Michael S; Khan, Asis; Lauron, Elvin J et al. (2015) Rhoptry Proteins ROP5 and ROP18 Are Major Murine Virulence Factors in Genetically Divergent South American Strains of Toxoplasma gondii. PLoS Genet 11:e1005434|
|Behnke, Michael S; Khan, Asis; Sibley, L David (2015) Genetic mapping reveals that sinefungin resistance in Toxoplasma gondii is controlled by a putative amino acid transporter locus that can be used as a negative selectable marker. Eukaryot Cell 14:140-8|
|MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M et al. (2015) Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. Elife 4:|
|Selleck, Elizabeth M; Orchard, Robert C; Lassen, Kara G et al. (2015) A Noncanonical Autophagy Pathway Restricts Toxoplasma gondii Growth in a Strain-Specific Manner in IFN-Î³-Activated Human Cells. MBio 6:e01157-15|
|Choi, Jayoung; Park, Sunmin; Biering, Scott B et al. (2014) The parasitophorous vacuole membrane of Toxoplasma gondii is targeted for disruption by ubiquitin-like conjugation systems of autophagy. Immunity 40:924-35|
|Dubey, J P; Van Why, K; Verma, S K et al. (2014) Genotyping Toxoplasma gondii from wildlife in Pennsylvania and identification of natural recombinants virulent to mice. Vet Parasitol 200:74-84|
|Etheridge, Ronald D; Alaganan, Aditi; Tang, Keliang et al. (2014) The Toxoplasma pseudokinase ROP5 forms complexes with ROP18 and ROP17 kinases that synergize to control acute virulence in mice. Cell Host Microbe 15:537-50|
Showing the most recent 10 out of 59 publications