PROJECT SUMMARY/ABSTRACT Despite the hostile environment of the bloodstream where the host immune system is highly active, schistosomes, parasitic flatworms that cause schistosomiasis that affects over 200 million individuals globally, have a remarkable ability to thrive inside the vasculature for over several decades. While the tegument (outer skin) has been shown to play an important role in parasite immune evasion, what remains a mystery is the mechanism by which parasites neutralize large amounts of immune components that they ingest from the host blood. Our recently published work reveals that the esophageal gland, an anterior accessory organ of parasite’s digestive tract, is essential for schistosomes to survive inside the bloodstream. It operates by lysing ingested immune cells before passing them into the gut, preventing them from accessing the inner parasite tissues. Such observations lead us to hypothesize that specific esophageal gland proteins block and/or degrade host immune components, thereby ensuring parasite survival. The main questions that we are interested in are: What are the roles of esophageal gland factors in degrading and/or blocking host immune components and how do such functions contribute to parasite survival? What is the mechanism of specific esophageal gland factors in parasite immune evasion? These will be investigated under three specific aims: 1) Define the esophageal gland cell types and genes; 2) Determine the role of specific esophageal gland factors in immune cell lysis and parasite survival; and 3) Determine the mechanism of specific esophageal gland factors in host-parasite interaction. In the first aim, we will systematically identify esophageal gland genes by comparing RNA-seq data between parasites with and without the esophageal gland tissue. In the second aim, we will functionally interrogate identified genes using RNAi coupled with an in vitro feeding assay, and determine the viability of candidate gene-deficient parasites inside the mammalian host. Preliminary results from these aims reveal dozens of esophageal gland factors, two of which appear to be essential for degrading host immune cells. Thus, in the third aim, we will determine the activity of the two candidate proteins, identify their binding partners, and decipher the mechanism of host-parasite interaction. Together, we expect to bring new insights to schistosomes’ esophageal gland-mediated immune evasion mechanism by identifying essential esophageal gland factors and their mode of action. The proposed study is innovative since our findings will likely shift the paradigm of schistosome immune evasion, which has been thought to be driven primarily by its tegument. Our study is significant since it bridges parasite developmental and translational biology by identifying essential esophageal gland molecules and understanding how they operate. These candidates may be exploited in the future as potential therapeutic targets that can complement pra...