Helminth defence molecules—immunomodulators designed by parasites!

HELMINTH DEFENCE MOLECULES (HDMs)—ANTIMICROBIALS OR IMMUNOMODULATORS? Parasitic helminths (worms) are one of the most successful animal groups in nature. They are large multicellular organisms and therefore cannot penetrate host cells but must reside inside tissue or organs. They infect over 1 billion people globally, mostly in tropical/sub-tropical regions, taking an enormous toll on animal and human health (Hotez et al., 2008). Although the main evolutionary driving force for parasitism may have been the ease of access to food this brought other challenges, most importantly the need to overcome expulsion by the immune responses of the host. Accordingly, helminths have evolved elaborate mechanisms to manage, suppress or manipulate the mammalian immune system. It is generally thought that worms influence the host immune response by secreting factors into their environment—the host parasite interface. Over the past 10 years the application of proteomics techniques has allowed us to identify molecules secreted by helminths. Although the exact complement of secretory molecules differs between species, most helminths release proteolytic enzymes with endoand exo-peptidase activities (Robinson et al., 2008a,b), antioxidants such as glutathione-S transferase and peroxiredoxin (Jefferies et al., 2001; Donnelly et al., 2008; Robinson et al., 2009) and other molecules with a range of biochemical activities including protease inhibitors and metabolic enzymes. Whilst the biological function of a few of these helminth molecules are well defined, this is generally restricted to those that possess evolutionarily conserved catalytic domains/active site residues that are easily identified using bioinformatics search tools (e.g., Fasciola cysteine proteases function in fluke nutrition; Lowther et al., 2009). However, many helminths also secrete a range of molecules whose primary sequences offer no clue as to their biochemical activity or biological function. During our on-going analysis of the secretory proteome (i.e., the secretome) of the helminth Fasciola hepatica, a parasite that infects its host via the intestine following ingestion and then migrates to the liver, we identified a novel and abundant 8 kDa protein. The protein contained a secretory signal peptide but BLAST analysis of its primary sequence failed to infer a function. However, structural studies revealed that a 37 amino acid C-terminal region adopted a similar secondary structure (amphipathic α-helix) to a number of peptides with known antimicrobial and/or immunomodulatory functions, most particularly mammalian LL-37 (Robinson et al., 2011). Phylogenetic analysis discovered that these secretory proteins are conserved across the major trematode species that collectively infect >1 billion humans, including the liver flukes Clonorchis sinensis, Paragonimus westermani, and Opisthorchis viverrini and the blood flukes Schistosoma mansoni and S. japonicum (Robinson et al., 2011). Accordingly, by analogy with the mammalian antimicrobial and/or immunomodulators we hypothesized that these helminth molecules may play a critical role in the parasites interaction with its host and thus named them helminth defence molecules (HDMs). This hypothesis, however, posed the question that is central to understanding how they may perform this function, namely, are HDMs antimicrobial or immunomodulatory peptides, or both?