Therapeutic potential of Fasciola hepatica-derived immunomodulatory peptides in the treatment of sepsis

Sepsis is a life-threatening syndrome characterised by dysregulated host responses to infection, that currently has limited effective immunomodulatory therapies. Helminths have evolved potent immune evasion strategies, partially through the secretion of Helminth Defense Molecules (HDMs). The present study investigated the immunomodulatory potential of Fasciola hepatica-HDMs, FhHDM-1 and a truncated variant, FhHDM-C2. This investigation primarily focused on their effects on lipopolysaccharide (LPS)-induced inflammation and inflammasome activation. In vitro experiments demonstrated a significant reduction in the production of the inflammatory cytokines tumour necrosis factor, interleukin 6 and interleukin 1-beta by murine macrophages, attributed to the modulation of LPS signalling and NLRP3 inflammasome activation. Furthermore, this project validated the in vivo murine caecal slurry model of polymicrobial sepsis and explored the potential of FhHDM-1 within this model, providing avenues for future experimentation. These findings highlight the need for further investigation into FhHDM peptides as promising candidates for sepsis therapy, including the optimisation of dosing, delivery mechanisms, and mechanism of action studies. Beyond their role in sepsis, the capacity of these peptides to regulate inflammatory responses may hold broader therapeutic relevance in conditions characterised by immune dysregulation.

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (Research Masters Theses)