Toxoplasma gondii sexual stage
The Apicomplexan parasite Toxoplasma gondii has a complex life cycle that includes an asexual stage and a sexual stage. In nature, the sexual stage occurs only in cats. Until recently, the reasons for this feline specificity were unknown. Our lab showed that inhibition of the mammalian enzyme delta-6-desaturase (D6D) and consequent elevation of its substrate linoleic acid (LA) can break the species barrier to enable T. gondii sexual development in non-feline hosts.
We are now following up on that finding by asking:
- How does lack of D6D activity enable T. gondii to enter its sexual stage?
- Does build-up of LA create lipid mediators that signal to T. gondii to enter sexual stage?
- What other host/parasite factors are required for T. gondii to undergo sexual reproduction?
- How does T. gondii sense the factors that trigger the switch to the sexual cycle?
We are using mice, mouse-derived organoids, and organoids derived from other species (e.g. cats) in conjunction with genetic, biochemical, and molecular biology tools to answer these questions.
Developing models for Entamoeba histolytica infection
Entamoeba histolytica is another single-celled eukaryotic intestinal parasite that causes diarrhea. E. histolytica is a challenging organism to work with in the laboratory, but the Knoll Lab recently developed a reliable animal model for an oral route of E. histolytica infection. We are further developing this model by characterizing pathology and parasite load in the intestine, and by building additional in vivo and in vitro tools to model invasive disease. Future work will enable us to identify host, parasite, and environmental factors that affect E. histolytica infection.
Understanding diseases caused by Cryptosporidium parvum infection
Cryptosporidium parvum is an Apicomplexan parasite that causes non-bloody diarrhea. It is also associated with colorectal cancer in humans and causes cancer in some mouse models. To understand how C. parvum causes acute intestinal disease and cancer, we are using RNA-seq and metabolomics to identify host and parasite factors that differentiate healthy from diseased states. Future efforts will determine the mechanisms by which these factors cause or limit C. parvum-induced disease.
Host factors in parasitic infections
Numerous host genes affect the outcomes of parasitic infection. We are interested in host immune genes that affect infection outcomes by modulating interferon responses (e.g. IFN-γ, ZBP1) and necroptosis (ZBP1, RIPK3). To understand how these genes alter parasite and/or host biology during infection, we first identify candidate molecular mechanisms by comparing parasite-infected knockout mice to their wildtype controls. We then use biochemical, molecular biology, and immunological tools to further dissect how these mechanisms work.
Recent advances in “omics” technologies enabled widespread collection of transcriptomic, proteomic, and metabolomic data that reveal the regulatory and biochemical landscapes of biological systems. Our lab has employed multi-omics to understand different facets of parasite biology, especially in T. gondii. Examples include discovery of host sex-specific differences in infection dynamics, identification of factors that differentiate acute and chronic infection, and new insights into microbial metabolism.
Parasites rely on their hosts to obtain nutrients, so it is not surprising that metabolic genes are often critical for parasites to grow, replicate, and disseminate throughout a host. Parasite metabolism can also alter host physiology and manipulate immune responses. We are interested in understanding the mechanisms by which parasite metabolism genes enable colonization and affect the host.
Toxoplasma gondii is an immensely successful parasite in the sense that once it colonize a host, the host is infected for life. T. gondii persists in the host tissues in cyst form, a unique lifestyle that requires many parasite adaptations. We want to determine which parasite and host genes enable persistent T. gondii infection and how those genes work.