Novel antiinflammatory biologics shaped by parasite-host coevolution

Area of Science:

• Parasitology
• Immunology
• Biotechnology

Background:

• Parasitic helminth infections are linked to reduced immune-mediated inflammatory diseases like inflammatory bowel diseases (IBD).
• Helminths possess immune-evasion strategies, utilizing their excretory-secretory (ES) products to modulate host immunity.
• Existing helminth-based therapies face challenges, necessitating alternative approaches.

Purpose of the Study:

• To develop a pipeline for discovering and validating helminth-derived immunomodulatory proteins as potential biologics.
• To screen a library of recombinant helminth ES proteins for anti-inflammatory properties, specifically against IBD.

Main Methods:

• Generation and in vivo screening of a recombinant cell-free secretome library from gastrointestinal hookworms.
• Expression of 78 recombinant ES proteins and in vitro screening in a mouse model of acute colitis.
• Validation of lead candidate proteins, including production in mammalian cells and ex vivo testing on IBD patient T cells.

Main Results:

• 20 out of 78 screened ES proteins demonstrated significant protection against colitis in mice.
• Identified lead candidates belong to diverse protein families: annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS.
• Validated proteins suppressed inflammatory cytokine secretion from IBD patient T cells ex vivo.

Conclusions:

• Helminth ES proteins represent a promising source for novel biologics targeting inflammatory diseases.
• The identified proteins offer a mechanistically differentiated and potentially safer therapeutic strategy for IBD and other inflammatory conditions.