research
schistosome life cycle:
two hosts, multiple body plans, single genome
After schistosomes infect a mammalian host through the skin, they are faced with epic existential challenges as they adapt to the new host environment: they must migrate into the bloodstream, begin to feed on blood, absorb nutrients for growth, and develop sexually for reproduction, all while withstanding the host immune system. Failure of any of these events would disrupt the parasite’s life cycle. However, the developmental mechanisms that endow schistosomes with such fascinating abilities to thrive inside the host remain largely unknown.
schistosome life cycle
I. How does esophageal gland mediate host immunity during blood feeding?
We recently discovered that the esophageal gland, an anterior accessory organ of the digestive tract, is required for schistosomes to survive inside the host. Schistosomes lacking the esophageal gland failed to block and degrade the immune cells that they ingest, leading to parasite death from the inside out. This work revealed a novel role of the esophageal gland that is essential for parasite survival through immune evasion.
Building upon these findings, we are characterizing the esophageal gland proteins and their functions, in order to define the esophageal gland-mediated immune evasion mechanism. We are taking a comparative transcriptomic approach coupled with high-throughput functional screening and biochemical assays to determine the function of esophageal gland proteins in tissue development and maintenance, immune cell lysis, interaction with host proteins, and parasite survival.
Relevant Reading:
The esophageal gland mediates host immune evasion by the human parasite Schistosoma mansoni.
Top: whole-mount colorimetric in situ hybridization of an esophageal gland gene in an adult male schistosome. Bottom: an adult male worm stained with Peanut Agglutinin that labels the esopohageal gland (green), Phalloidin that outlines the esopohagus and the gut (red), and DAPI that labels the parasite cells and host immune cells inside the gut (blue).
II. what are the gene regulatory mechanisms of stem cell-driven tissue development and host-parasite interaction?
Recent work has revealed the importance of schistosome stem cells in homeostasis and reproduction that perpetuate the disease. In particular, we discovered that mammalian stage stem cells arise in cercarial body during embryogenesis (inside snail host) and only begin to proliferate 1-2 days after entering the mammalian host skin, revealing the key aspect of parasite transmission.
These handful of larval stem cells must differentiate into various cell types; this process is likely regulated by tissue-specific transcription factors. For instance, FoxA regulates the development and maintenance of the esophageal gland. However, we do not know anything about the identity and function of developmental regulators in other parasite tissues such as neurons and muscles. These cell types likely play essential roles for parasites to transition across the host environment (e.g., from skin to vasculature), use existing cells as backbones for prospective development of respective tissues, and relay extrinsic cues for stem cell-driven organ development. In fact, in our skin-stage schistosomula scRNA-seq, neural and muscle cells are abundant and heterogeneous, hinting to their important functional role in early intra-mammalian transition and development.
Building upon these findings, we aim to characterize tissue-specific developmental regulators and their functions in tissue development and maintenance including muscles and neurons. Furthermore, using large-scale RNAi screening followed by parasite transplantation, we will determine the functions of specific cell types and genes in schistosome development, survival, and host-parasite interaction.
Relevant Readings:
1) Stem cell heterogeneity drives the parasitic life cycle of Schistosoma mansoni
2) Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni.
Top: fluorescence in situ hybridization of a stem cell gene (h2b) in cercaria and EdU pulse detection in transformed schistosomula. Figures adapted from: Lee et al., 2020; Wang et al., 2018. Bottom: single-cell RNA-seq of skin-stage schistosomula. Figure adapted from: Diaz Soria and Lee et al., 2020.
III. Developing new tools to investigate schistosome development and host-parasite interaction
Currently, the lack of an in vitro system that better mimics the host environment precludes us from understanding the mechanisms that regulate schistosome transitions across host environments (i.e., migration from skin to bloodstream) and host-parasite interactions throughout their journey.
In collaboration with bioengineers, we successfully created a prototype device that can potentially capture schistosomula migrating into the blood vessel. We are interested in such an interdisciplinary approach to create novel in vitro platforms that better recapitulates host environment, in order to tease apart parasite developmental mechanisms and better understand host-parasite interactions.