Treatment with alpha-galactosylceramide before Trypanosoma cruzi infection provides protection or induces failure to thrive.
Trypanosoma cruzi, a protozoan parasite, chronically infects many mammalian species and triggers a chronic inflammatory disease. Invariant Valpha14 NK T (iNKT) cells are a regulatory subset of T cells that can contribute to protection against pathogens and to control of chronic inflammatory diseases. alpha-Galactosylceramide (alpha-GalCer) is an iNKT cell-specific glycolipid Ag: a single immunization with alpha-GalCer stimulates robust IFN-gamma and IL-4 production by iNKT cells, while multiple immunizations stimulate IL-4 production, but limited IFN-gamma production. We recently demonstrated that iNKT cells help control T. cruzi infection and affect the chronic Ab response. Therefore, alpha-GalCer treatment might be used to increase protection or decrease chronic inflammation during T. cruzi infection. In this report, we show that a single dose of alpha-GalCer before T. cruzi infection decreases parasitemia. This protection is independent of IL-12, but dependent upon iNKT cell IFN-gamma. In addition, alpha-GalCer treatment of the IFN-gamma(-/-) mice exacerbates parasitemia through IL-4 production. Furthermore, a multiple dose regimen of alpha-GalCer before T. cruzi infection does not lower parasitemia and, surprisingly, after parasitemia has resolved, causes poor weight gain. These data demonstrate that during T. cruzi infection glycolipids can be used to manipulate iNKT cell responses and suggest the possibility of developing glycolipid treatments that can increase protection and possibly decrease the chronic inflammatory pathology.
Duthie
Malcolm S
MS
Infectious Disease Research Institute, Seattle, WA 98104, USA. mduthie@idri.org
Kahn
Stuart J
SJ
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D014355:Chagas Disease / Q000517:prevention & control*; D005183:Failure to Thrive / Q000139:chemically induced*; D005699:Galactosylceramides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000517:prevention & control
D000913:Antibodies, Protozoan; D005699:Galactosylceramides; D018664:Interleukin-12; D007371:Interferon-gamma