The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages.
The NLRP3 inflammasome is a multimeric protein complex that controls the production of IL-1β, a cytokine that influences the development of both innate and adaptive immune responses. Helminth parasites secrete molecules that interact with innate immune cells, modulating their activity to ultimately determine the phenotype of differentiated T cells, thus creating an immune environment that is conducive to sustaining chronic infection. We show that one of these molecules, FhHDM-1, a cathelicidin-like peptide secreted by the helminth parasite, Fasciola hepatica, inhibits the activation of the NLRP3 inflammasome resulting in reduced secretion of IL-1β by macrophages. FhHDM-1 had no effect on the synthesis of pro-IL-1β. Rather, the inhibitory effect was associated with the capacity of the peptide to prevent acidification of the endolysosome. The activation of cathepsin B protease by lysosomal destabilization was prevented in FhHDM-1-treated macrophages. By contrast, peptide derivatives of FhHDM-1 that did not alter the lysosomal pH did not inhibit secretion of IL-1β. We propose a novel immune modulatory strategy used by F. hepatica, whereby secretion of the FhHDM-1 peptide impairs the activation of NLRP3 by lysosomal cathepsin B protease, which prevents the downstream production of IL-1β and the development of protective T helper 1 type immune responses that are detrimental to parasite survival.-Alvarado, R., To, J., Lund, M. E., Pinar, A., Mansell, A., Robinson, M. W., O'Brien, B. A., Dalton, J. P., Donnelly, S. The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages.
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Raquel
R
Alvarado
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Joyce
J
To
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Maria E
ME
Lund
Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; and.
Anita
A
Pinar
Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; and.
Ashley
A
Mansell
School of Biological Sciences, Queen's University, Belfast, Northern Ireland.
Mark W
MW
Robinson
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Bronwyn A
BA
O'Brien
School of Biological Sciences, Queen's University, Belfast, Northern Ireland.
John P
JP
Dalton
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia; sheila.donnelly@uts.edu.au.
Sheila
S
Donnelly
D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005210:Fasciola hepatica / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D012822:Silicon Dioxide / Q000633:toxicity
D016207:Cytokines; D015801:Helminth Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012822:Silicon Dioxide; D002401:Cathepsin B
IL-1β; liver fluke; lysosome; trematode