Schistosome esophageal gland factor MEG-8.2 drives host cell lysis and interacts with host immune proteins

TL;DR

A protein called MEG-8.2 in schistosomes helps destroy host blood cells and interacts with immune proteins, aiding the parasite's survival.

Contribution

Identification of MEG-8.2 as a key factor in schistosome immune evasion through host cell lysis and immune protein interaction.

Findings

MEG-8.2 domains can lyse host blood cells in a concentration-dependent manner.

MEG-8.2 interacts with host proteins involved in immune activation.

MEG-8.2 plays a dual role in cell lysis and immune evasion.

Abstract

Schistosomes are blood flukes that ingest large amounts of host blood during their intra-mammalian stage. The ingested blood contains leukocytes that can be harmful, yet the parasites survive inside the host for decades, reflecting superb immune evasion mechanisms that remain poorly understood. Our previous work discovered that FoxA, a forkhead transcription factor, drives the production of the esophageal gland, an anterior digestive organ essential for degrading ingested leukocytes and for in vivo survival. However, a comprehensive molecular makeup of the esophageal gland remains unclear. Importantly, the esophageal gland factors responsible for degrading ingested leukocytes, their mechanisms of action, and how such a function relates to parasite survival and immune evasion remain unknown. Here, we identify additional esophageal gland genes by taking a comparative transcriptomics approach to identify transcripts altered in foxA knockdown adult schistosomes. A targeted RNAi screen coupled with biochemistry reveals that specific domains of the micro-exon gene MEG-8.2, can drive host cell lysis in a concentration-dependent manner. Using pull-down assays coupled with mass spectrometry, we discover that MEG-8.2 interacts with several host membrane and extracellular proteins that play important roles in activating innate and/or adaptive immunity. Together, our findings suggest a dual role for MEG-8.2 in effectively lysing the ingested cells in the esophageal lumen and interacting with specific host proteins to neutralize or suppress host immunity. These findings lay an important foundation for exploiting esophageal gland factors to treat schistosomiasis.

Schistosomiasis is a major parasitic disease that affects over 200 million people. Schistosomes’ ability to thrive inside the hostile environment of the host bloodstream and reproduce is the root cause of the disease. One potential source of such an ability comes from an elusive mechanism that neutralizes harmful immune components ingested during blood feeding. Previously, we discovered that a forkhead transcription factor, FoxA, drives the production of the esophageal gland, an anterior digestive organ essential for degrading ingested host leukocytes and for in vivo parasite survival. Here, we use foxA RNAi parasites to comprehensively identify esophageal gland factors. Using a targeted RNAi screen coupled with biochemistry, we discover that a specific domain of MEG-8.2, a micro-exon gene family protein, is necessary and sufficient to directly lyse host blood cells in a concentration-dependent manner. Furthermore, using pull-down mass spectrometry and protein modeling, we find that specific MEG-8.2 domains play an essential role in interacting with specific host proteins with known roles in immune activation. Our findings propose a dual role for MEG-8.2: concentration-dependent lysis of the host blood cell membrane and interaction with host proteins essential for the proper functioning of immune defense.

Figures