Abstract
Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts' own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation.
Highlights
Chronic helminth infections are known to be accompanied by various immunomodulatory processes
We have previously reported on the immunomodulatory activity of proteins collected from Ts larval stage 1 (L1) which interfere with CD4+ T cell priming and clinical parameters of experimental airway hyperreactivity [34]
Our findings further reveal that T. suis chitinase treatment of allergic mice inhibited host acidic mammalian chitinase (AMCase) expression on mRNA level and interfered with host chitinase activity in the bronchoalveolar lavage (BAL) fluid, suggesting an alternative mechanism that might involve the high degree of structural similarity between host and nematode chitinases
Summary
Chronic helminth infections are known to be accompanied by various immunomodulatory processes. Research has focused on identifying secreted helminth immunomodulators and mechanisms of suppression in order to understand natural infection and in parallel with the aim to exploit this knowledge for the benefit of unwanted human inflammatory diseases. As T. suis can be maintained in pigs but cannot multiply in humans, its administration as live parasite (TSO therapy) has been tested in a variety of clinical studies to improve human immune disorders (reviewed in [22]). Success stories of treatments of ulcerative colitis (UC) and Crohn’s disease (CD) with TSO [23,24,25] were followed by larger trials with only modest results for various autoimmune diseases [22, 26,27,28] and implicated the need for a greater understanding for the immunomodulatory mechanisms. In a rather small cohort of MS patients receiving controlled TSO treatment, we demonstrated varying degrees of parasite-specific T cell responses and cellular functionality across individuals receiving treatment, indicating the need to understand responders and nonresponders in order to develop more tailored treatment regimens [29]
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