Abstract
BackgroundAvian schistosomes, the causative agents of human cercarial dermatitis (or swimmer’s itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity.MethodsInducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate.ResultsiNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo.ConclusionsReactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.
Highlights
Avian schistosomes, the causative agents of human cercarial dermatitis, die in mammals but the mechanisms responsible for parasite elimination are unknown
Trichobilharzia regenti triggered nitric oxide (NO) production in the skin and 3‐NT formation in the spinal cord We first assessed the presence of inducible NO synthase (iNOS) and 3-NT in the skin and the spinal cord which are affected by T. regenti migration
A strong iNOS signal was observed in the epidermal cells around 80% of schistosomula and in the adjacent skin superficial area (Fig. 1)
Summary
The causative agents of human cercarial dermatitis (or swimmer’s itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. We examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity. Reactive nitrogen species (RNS), such as nitric oxide (NO) or peroxynitrite (ONOO−), are essential antimicrobial molecules of the innate immunity [1, 2]. Apart from the wellknown antimicrobial effects on parasitic protists, e.g. Leishmania, Toxoplasma, Giardia or Trypanosoma cruzi [7,8,9,10], RNS participate in the control of infections caused by multicellular helminths, like schistosomes (blood flukes). Non-permissive hosts of Schistosoma japonicum, the high innate expression of iNOS was recently shown to block parasite growth, development of reproductive organs and egg formation, identifying NO as a key factor of the inherent resistance [14]. Considering the antiparasitic capacity of NO, novel antischistosomal therapeutics combining the traditional drug praziquantel with NOreleasing compounds were developed [20]
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