Parasitic helminth
infections, while a major cause of
neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as
inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth
infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES)
complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory
proteins. We successfully expressed 78 recombinant ES
proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute
colitis. After statistical filtering and ranking, 20
proteins conferred significant protection against various parameters of
colitis. Lead candidates from distinct
protein families, including
annexins, transthyretins, nematode-specific
retinol-binding proteins, and SCP/TAPS were identified. Representative
proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory
cytokine secretion by T cells from IBD patient colon biopsies.
Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.