Investigating the immunomodulatory properties of hookworm excretory/secretory (ES) products

Chronic inflammatory conditions, such as inflammatory bowel diseases, are becoming increasingly common around the world. Concurrently there is a decrease in childhood exposure to microbes and parasites due to increased sanitation in industrialised nations and urban settings. The hygiene hypothesis, suggests that there may be a link between reduced exposures to pathogens during early childhood and chronic inflammatory conditions later in life. The 'old friends' hypothesis further suggests that parasites and microbes that were common during early human evolution, have played a role in the formation of the immune system and by removing these stimuli (with increasingly sanitary living conditions) we are perhaps removing an essential part of the immune education pathway. Parasites themselves have had to evolve certain mechanisms which allow them to evade immune surveillance from their hosts. Based on these concepts I hypothesized that the excretory/secretory products of the dog hookworm Ancylostoma caninum (AcES) could be utilized for modulating immune responses in mice that were concurrently exposed to chemicals which induce an inflammatory colitis. AcES when administered to naïve mice, was able to skew the immune response towards a type 2 phenotype. Mice treated with AcES exhibited high levels of IL-4, IL-5 and IL-10 as well as eosinophilia, demonstrating that a live hookworm infection was not necessary to induce a type 2 immune response common to many helminth infections. Furthermore, under the pro-inflammatory setting of chemically induced mouse models of colitis, AcES administration significantly reduced weight loss, tissue damage and pro-inflammatory cytokines IL-17A and IFNγ. The work present herein highlights the potential involvement of myeloid derived suppressor cells (MDSCs) in mediating AcES induced amelioration of colitis. It further demonstrates that in the DSS (dextran sulphate sodium) model of colitis, the mechanism of action of AcES is not dependent on IL-10 nor the presence of T and B cells. A single recombinantly expressed protein that is naturally found in AcES is also shown to be extremely potent at reducing inflammation in the TNBS model of colitis. These results suggests that the hookworm is actively secreting compounds that can alter the host's immune response, providing a multitude of naturally occurring immunomodulators that could be harnessed for use as therapeutics in a range of different inflammatory conditions