MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans

Eur J Immunol. 2005 Mar;35(3):870-8. doi: 10.1002/eji.200425799.

Abstract

We investigated here the potential role of Toll-like receptors (TLR) and the adaptor protein MyD88 in innate immunity responses to Cryptococcus neoformans, a pathogenic encapsulated yeast. Peritoneal macrophages from MyD88(-/-) or TLR2(-/-) mice released significantly less TNF-alpha, compared with wild-type controls, after in vitro stimulation with whole yeasts. In contrast, no differences in TNF-alpha release were noted between macrophages from C3H/HeJ mice, which have a loss of function mutation in TLR4, relative to C3H/HeN controls. When MyD88- or TLR2-deficient mice were infected with low doses of the H99 serotype A strain, all of the control animals, but none of MyD88(-/-) and only 38% of the TLR2(-/-) animals survived, in association with higher fungal burden in the mutant mice. Both MyD88(-/-) and TLR2(-/-) animals showed decreased TNF-alpha, IL-12p40 and/or IFN-gamma expression in various organs during infection. No difference in susceptibility to experimental cryptococcosis was found between C3H/HeJ mice and C3H/HeN controls. In conclusion, our data indicate that TLR2 and MyD88, but not TLR4, critically contribute to anti-cryptococcal defenses through the induction of increased TNF-alpha, IL-12 and IFN-gamma expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, Differentiation / immunology*
  • Cryptococcosis / immunology*
  • Cryptococcus neoformans / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / biosynthesis
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Myeloid Differentiation Factor 88
  • RNA, Messenger / analysis
  • Receptors, Cell Surface / immunology*
  • Receptors, Immunologic / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma