Abstract
We hypothesized that unrecognized differences in epithelial expression of inducible nitric oxide synthase (iNOS), resulting from engineered immunodeficiency, could explain the contradictory findings of prior studies regarding the importance of nitric oxide (NO) in murine models of Cryptosporidium parvum infection. Severe combined immunodeficient mice (SCID) failed to constitutively or inducibly express epithelial iNOS or increase NO synthesis in response to C. parvum infection. In contrast, mice lacking IFN-γ alone induced both epithelial iNOS expression and NO synthesis in response to infection. Accordingly, lymphocytes mediate epithelial expression of iNOS and NO synthesis independent of IFN-γ in response to C. parvum infection. These findings in large part explain the contradictory conclusions of prior studies regarding the role of iNOS in C. parvum infection.
References
Culshaw RJ, Bancroft GJ, McDonald V (1997) Gut intraepithelial lymphocytes induce immunity against Cryptosporidium infection through a mechanism involving gamma interferon production. Infect Immun 65:3074–3079
Gookin JL, Rhoads JM, Argenzio RA (2002) Inducible nitric oxide synthase mediates early epithelial repair of porcine ileum. Am J Physiol Gastrointest Liver Physiol 283:G157–G168
Gookin JL, Allen J, Chiang S, Duckett L, Armstrong MU (2005) Local peroxynitrite formation contributes to early control of Cryptosporidium parvum infection. Infect Immun 73:3929–3936
Gookin JL, Chiang S, Allen J, Armstrong MU, Stauffer SH, Finnegan C, Murtaugh MP (2006) NF-{kappa}B-mediated expression of iNOS promotes epithelial defense against infection by Cryptosporidium parvum in neonatal piglets. Am J Physiol Gastrointest Liver Physiol 290:G164–G174
Hayward AR, Chmura K, Cosyns M (2000) Interferon-gamma is required for innate immunity to Cryptosporidium parvum in mice. J Infect Dis 182:1001–1004
Hoffman RA (2000) Intraepithelial lymphocytes coinduce nitric oxide synthase in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 278:G886–G894
Hoffman RA, Zhang G, Nussler NC, Gleixner SL, Ford HR, Simmons RL, Watkins SC (1997) Constitutive expression of inducible nitric oxide synthase in the mouse ileal mucosa. Am J Physiol 272:G383–G392
Kuhls TL, Mosier DA, Abrams VL, Crawford DL, Greenfield RA (1994) Inability of interferon-gamma and aminoguanidine to alter Cryptosporidium parvum infection in mice with severe combined immunodeficiency. J Parasitol 80:480–485
Lacroix S, Mancassola R, Naciri M, Laurent F (2001) Cryptosporidium parvum-specific mucosal immune response in C57BL/6 neonatal and gamma interferon-deficient mice: role of tumor necrosis factor alpha in protection. Infect Immun 69:1635–1642
Lean IS, McDonald SA, Bajaj-Elliott M, Pollok RC, Farthing MJ, McDonald V (2003) Interleukin-4 and transforming growth factor beta have opposing regulatory effects on gamma interferon-mediated inhibition of Cryptosporidium parvum reproduction. Infect Immun 71:4580–4585
Leitch GJ, He Q (1994) Arginine-derived nitric oxide reduces fecal oocyst shedding in nude mice infected with Cryptosporidium parvum. Infect Immun 62:5173–5176
Leitch GJ, He Q (1999) Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model. Infect Immun 67:5885–5891
McDonald V, Robinson HA, Kelly JP, Bancroft GJ (1996) Immunity to Cryptosporidium muris infection in mice is expressed through gut CD4+ intraepithelial lymphocytes. Infect Immun 64:2556–2562
Pollok RC, Farthing MJ, Bajaj-Elliott M, Sanderson IR, McDonald V (2001) Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum. Gastroenterology 120:99–107
Waters WR, Reinhardt TA, Harp JA (1997) Oral administration of putrescine inhibits Cryptosporidium parvum infection of neonatal C57BL-6 mice and is independent of nitric oxide synthesis. J Parasitol 83:746–750
Acknowledgments
This work was supported by the National Institutes of Health (P30 DK034987) from the National Institute of Diabetes, Digestive Diseases and Kidney. We thank Maria R. Stone, Martha U. Armstrong, and Marjory Gray for their technical assistance.
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Nordone, S.K., Gookin, J.L. Lymphocytes and not IFN-γ mediate expression of iNOS by intestinal epithelium in murine cryptosporidiosis. Parasitol Res 106, 1507–1511 (2010). https://doi.org/10.1007/s00436-010-1837-7
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DOI: https://doi.org/10.1007/s00436-010-1837-7