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. 1997 Jan;65(1):219–226. doi: 10.1128/iai.65.1.219-226.1997

Developmental differences determine larval susceptibility to nitric oxide-mediated killing in a murine model of vaccination against Schistosoma mansoni.

S F Ahmed 1, I P Oswald 1, P Caspar 1, S Hieny 1, L Keefer 1, A Sher 1, S L James 1
PMCID: PMC174579  PMID: 8975915

Abstract

A persistent paradox in our understanding of protective immunity against Schistosoma mansoni infection in animals vaccinated with attenuated parasites has been that attrition of challenge parasites occurs during migration through the lungs in vivo, although parasites recovered from the lungs appear to be relatively resistant to cytotoxic effector mechanisms in vitro. We have compared the susceptibilities of different stages of larvae to killing by nitric oxide (NO), which was previously shown to be involved in the larvicidal function of cytokine-activated cytotoxic effector cells. Lung-stage larvae obtained 1 week after infection were not killed in vitro by NO generated either by a chemical NO donor or by activated cells. In contrast, parasites obtained from the portal system of control mice or from the lungs of vaccinated mice 2.5 weeks following challenge infection were killed by NO. As previously shown for mammalian cell targets, the effects of NO in susceptible larval stages may involve enzymes required for aerobic energy metabolism, since similar cytotoxicity was demonstrated by chemical inhibitors of the citric acid cycle or mitochondrial respiration. Taken together with previous observations of enhanced Th1 activity and expression of NO synthase in the lungs of vaccinated mice at 2.5 weeks after challenge infection, these observations elucidate the immune mechanism of vaccine-induced resistance to S. mansoni infection. Moreover, they suggest that conversion to a less metabolically active state may allow pathogens to escape the effects of the important effector molecule NO.

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Selected References

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  1. Barrett J. The anaerobic end-products of helminths. Parasitology. 1984 Feb;88(Pt 1):179–198. doi: 10.1017/s0031182000054445. [DOI] [PubMed] [Google Scholar]
  2. Beckman J. S., Beckman T. W., Chen J., Marshall P. A., Freeman B. A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620–1624. doi: 10.1073/pnas.87.4.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bohne W., Heesemann J., Gross U. Reduced replication of Toxoplasma gondii is necessary for induction of bradyzoite-specific antigens: a possible role for nitric oxide in triggering stage conversion. Infect Immun. 1994 May;62(5):1761–1767. doi: 10.1128/iai.62.5.1761-1767.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brophy P. M., Pritchard D. I. Immunity to helminths: Ready to tip the biochemical balance? Parasitol Today. 1992 Dec;8(12):419–422. doi: 10.1016/0169-4758(92)90195-8. [DOI] [PubMed] [Google Scholar]
  5. Dean D. A., Mangold B. L. Evidence that both normal and immune elimination of Schistosoma mansoni take place at the lung stage of migration prior to parasite death. Am J Trop Med Hyg. 1992 Aug;47(2):238–248. doi: 10.4269/ajtmh.1992.47.238. [DOI] [PubMed] [Google Scholar]
  6. Dean D. A., Mangold B. L., Georgi J. R., Jacobson R. H. Comparison of Schistosoma mansoni migration patterns in normal and irradiated cercaria-immunized mice by means of autoradiographic analysis. Evidence that worm elimination occurs after the skin phase in immunized mice. Am J Trop Med Hyg. 1984 Jan;33(1):89–96. doi: 10.4269/ajtmh.1984.33.89. [DOI] [PubMed] [Google Scholar]
  7. Foster L. A., Chen G. Z., VandeWaa E. A., Pax R. A., Bennett J. L. Glutamine- vs glucose-supported motor activity in Schistosoma mansoni: physiological relevance of aerobic metabolism. Exp Parasitol. 1989 Jul;69(1):44–53. doi: 10.1016/0014-4894(89)90170-7. [DOI] [PubMed] [Google Scholar]
  8. James S. L., Boros D. L. Immune effector role of macrophages in experimental schistosomiasis mansoni. Immunol Ser. 1994;60:461–473. [PubMed] [Google Scholar]
  9. James S. L. Experimental models of immunization against schistosomes: lessons for vaccine development. Immunol Invest. 1992 Aug;21(5):477–493. doi: 10.3109/08820139209069385. [DOI] [PubMed] [Google Scholar]
  10. James S. L., Glaven J. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J Immunol. 1989 Dec 15;143(12):4208–4212. [PubMed] [Google Scholar]
  11. Kassim O. O., Dean D. A., Mangold B. L., Von Lichtenberg F. Combined microautoradiographic and histopathologic analysis of the fate of challenge Schistosoma mansoni schistosomula in mice immunized with irradiated cercariae. Am J Trop Med Hyg. 1992 Aug;47(2):231–237. doi: 10.4269/ajtmh.1992.47.231. [DOI] [PubMed] [Google Scholar]
  12. Lazdins J. K., Stein M. J., David J. R., Sher A. Schistosoma mansoni: rapid isolation and purification of schistosomula of different developmental stages by centrifugation on discontinuous density gradients of Percoll. Exp Parasitol. 1982 Feb;53(1):39–44. doi: 10.1016/0014-4894(82)90090-x. [DOI] [PubMed] [Google Scholar]
  13. Mastin A. J., Bickle Q. D., Wilson R. A. Schistosoma mansoni: migration and attrition of irradiated and challenge schistosomula in the mouse. Parasitology. 1983 Aug;87(Pt 1):87–102. doi: 10.1017/s0031182000052446. [DOI] [PubMed] [Google Scholar]
  14. McLaren D. J., James S. L. Ultrastructural studies of the killing of schistosomula of Schistosoma mansoni by activated macrophages in vitro. Parasite Immunol. 1985 May;7(3):315–331. doi: 10.1111/j.1365-3024.1985.tb00079.x. [DOI] [PubMed] [Google Scholar]
  15. Mooradian D. L., Hutsell T. C., Keefer L. K. Nitric oxide (NO) donor molecules: effect of NO release rate on vascular smooth muscle cell proliferation in vitro. J Cardiovasc Pharmacol. 1995 Apr;25(4):674–678. [PubMed] [Google Scholar]
  16. Oswald I. P., Eltoum I., Wynn T. A., Schwartz B., Caspar P., Paulin D., Sher A., James S. L. Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):999–1003. doi: 10.1073/pnas.91.3.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pearce E. J., James S. L. Post lung-stage schistosomula of Schistosoma mansoni exhibit transient susceptibility to macrophage-mediated cytotoxicity in vitro that may relate to late phase killing in vivo. Parasite Immunol. 1986 Sep;8(5):513–527. doi: 10.1111/j.1365-3024.1986.tb00866.x. [DOI] [PubMed] [Google Scholar]
  18. Sher A., James S. L., Simpson A. J., Lazdins J. K., Meltzer M. S. Macrophages as effector cells of protective immunity in murine schistosomiasis. III. Loss of susceptibility to macrophage-mediated killing during maturation of S. mansoni schistosomula from the skin to the lung stage. J Immunol. 1982 Apr;128(4):1876–1879. [PubMed] [Google Scholar]
  19. Sher A., Moser G. Schistosomiasis: immunologic properties of developing schistosomula. Am J Pathol. 1981 Jan;102(1):121–126. [PMC free article] [PubMed] [Google Scholar]
  20. Skelly P. J., Stein L. D., Shoemaker C. B. Expression of Schistosoma mansoni genes involved in anaerobic and oxidative glucose metabolism during the cercaria to adult transformation. Mol Biochem Parasitol. 1993 Jul;60(1):93–104. doi: 10.1016/0166-6851(93)90032-s. [DOI] [PubMed] [Google Scholar]
  21. Smithers S. R., Terry R. J. The infection of laboratory hosts with cercariae of Schistosoma mansoni and the recovery of the adult worms. Parasitology. 1965 Nov;55(4):695–700. doi: 10.1017/s0031182000086248. [DOI] [PubMed] [Google Scholar]
  22. Smythies L. E., Coulson P. S., Wilson R. A. Monoclonal antibody to IFN-gamma modifies pulmonary inflammatory responses and abrogates immunity to Schistosoma mansoni in mice vaccinated with attenuated cercariae. J Immunol. 1992 Dec 1;149(11):3654–3658. [PubMed] [Google Scholar]
  23. Stamler J. S., Singel D. J., Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 1992 Dec 18;258(5090):1898–1902. doi: 10.1126/science.1281928. [DOI] [PubMed] [Google Scholar]
  24. Thompson D. P., Morrison D. D., Pax R. A., Bennett J. L. Changes in glucose metabolism and cyanide sensitivity in Schistosoma mansoni during development. Mol Biochem Parasitol. 1984 Sep;13(1):39–51. doi: 10.1016/0166-6851(84)90100-2. [DOI] [PubMed] [Google Scholar]
  25. Tielens A. G. Energy generation in parasitic helminths. Parasitol Today. 1994 Sep;10(9):346–352. doi: 10.1016/0169-4758(94)90245-3. [DOI] [PubMed] [Google Scholar]
  26. Vanden Bossche H. How anthelmintics help us to understand helminths. Parasitology. 1985 Apr;90(Pt 4):675–685. doi: 10.1017/s0031182000052306. [DOI] [PubMed] [Google Scholar]
  27. Williams M. E., Caspar P., Oswald I., Sharma H. K., Pankewycz O., Sher A., James S. L. Vaccination routes that fail to elicit protective immunity against Schistosoma mansoni induce the production of TGF-beta, which down-regulates macrophage antiparasitic activity. J Immunol. 1995 May 1;154(9):4693–4700. [PubMed] [Google Scholar]
  28. Wilson R. A., Coulson P. S. Lung-phase immunity to Schistosomes: a new perspective on an old problem? Parasitol Today. 1989 Sep;5(9):274–278. doi: 10.1016/0169-4758(89)90017-3. [DOI] [PubMed] [Google Scholar]
  29. Woods M. L., 2nd, Mayer J., Evans T. G., Hibbs J. B., Jr Antiparasitic effects of nitric oxide in an in vitro murine model of Chlamydia trachomatis infection and an in vivo murine model of Leishmania major infection. Immunol Ser. 1994;60:179–195. [PubMed] [Google Scholar]
  30. Wynn T. A., Oswald I. P., Eltoum I. A., Caspar P., Lowenstein C. J., Lewis F. A., James S. L., Sher A. Elevated expression of Th1 cytokines and nitric oxide synthase in the lungs of vaccinated mice after challenge infection with Schistosoma mansoni. J Immunol. 1994 Dec 1;153(11):5200–5209. [PubMed] [Google Scholar]
  31. van Oordt B. E., Tielens A. G., van den Bergh S. G. The energy metabolism of Schistosoma mansoni during its development in the hamster. Parasitol Res. 1988;75(1):31–35. doi: 10.1007/BF00931187. [DOI] [PubMed] [Google Scholar]

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