Defining the mechanisms and therapeutic potential of Helminth-derived Immunomodulatory Peptides

The discovery of helminth defence molecules (HDMs) represented a family of proteins with distinctive features analogous to cathelicidins. The <i>Fasciola hepatica</i> HDM (FhHDM-1) significantly modulates macrophage function and has regulates inflammation in several preclinical models of allergic and autoimmune disease.<br> <br>This thesis has provided further insight into the role of FhHDM-1 in inflammation in vitro and in vivo.

We have also revealed the potential of FhHDM-1.C2, a 40mer C-terminal derivative of the FhHDM-1 sequence, as a potential therapeutic in our model of acute lung injury with comparable effects to the native sequence peptide. Our studies conclude that FhHDM-1 targets AMPK signalling in macrophages and in lung tissue during inflammation. In an <i>in vivo</i> model of pulmonary <i>Pseudomonas aeruginosa</i> infection, we found FhHDM-1 mediated the recruitment of phagocytic cells which was accompanied by increased bacterial clearance in the lung although FhHDM-1.C2 only partially replicated these effects.<br> <br>We propose that FhHDM-1 is a critical mediator of anti-microbial responses in the lung and has potential as a therapeutic for acute infection.