Zhicheng Dou
Assistant Professor
Email: zdou@clemosn.edu
Website: http://doulab.net/
Education:
Ph.D., Chemistry and Biochemistry, University of Southern Mississippi, 2009
B.S., Life Sciences, Fudan University, 2002
My research focuses on proteolytic mechanisms during infection by the obligate intracellular parasite Toxoplasma gondii. T. gondii is globally distributed and human seroprevalence is as high as 78% in some countries. In the United States, 15-20% of the population is infected with Toxoplasma, imposing a health care burden of at least $3 billion in 2012. The infection causes toxoplasmosis, affecting the eyes, brain, and heart of the people with a weakened immune system, including AIDS patients and organ transplant recipients. Toxoplasmosis is also responsible for congenital birth defects resulting from mother-to-child transmission during pregnancy. T. gondii infection has also gained considerable public attention for its ability to manipulate animal behavior and its association with major mental illnesses including schizophrenia. Nonetheless, pathogenic mechanisms underlying toxoplasmosis remain poorly understood. The absence of such knowledge precludes development of novel strategies to manage T. gondii infection and minimize disease. During intracellular growth T. gondii requires access to host cell metabolites to support its replication. Our recent findings published in mBio unexpectedly revealed for the first time that the Toxoplasma parasite ingests host-derived proteins into its endocytic system and delivers them to a recently discovered vacuolar compartment (VAC). The VAC is an acidic organelle and is probably the terminal compartment of the parasite endolysosomal system. Incorporated host proteins accumulate within Toxoplasma cathepsin L (TgCPL)-deficient parasites, indicating that this major endopeptidase within the VAC plays an important role in digesting exogenous proteins. My work also showed that TgCPL-deficient parasites are attenuated in replication and virulence during the acute phase of infection. Strikingly, mice infected with a TgCPL null strain also have many fewer parasites during the chronic phase of infection. The findings suggest that the VAC functionally mirrors a lysosome for catabolism of proteins and potentially other macromolecules such as lipids and polysaccharides. This pathway also resembles the Plasmodium hemoglobin uptake pathway, which is the target of virtually all clinically effective antimalarials in use today. The long-term goal of my research is a detailed mechanistic understanding of how T. gondii internalizes host cellular proteins and digests them to support its intracellular replication. Using a combination of molecular biology, biochemistry and cell biological approaches, my laboratory will study the mechanistic underpinnings of acquisition and utilization of host macromolecules by Toxoplasma through its endocytic pathway. I also plan to use the sophisticated systems biology and metabolomics strategies to comprehensively dissect metabolic pathways in Toxoplasma parasites. The work is not only important for understanding how parasites acquire nutrients from host cells, but also to identify targets in the parasite nutrient pathway that may be susceptible to therapeutic intervention.
