MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans.
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.
Biondo
Carmelo
C
Department of Pathology and Experimental Microbiology, University of Messina, Messina, Italy.
Midiri
Angelina
A
Messina
Luciano
L
Tomasello
Francesco
F
Garufi
Gabriella
G
Catania
Maria Rosaria
MR
Bombaci
Mauro
M
Beninati
Concetta
C
Teti
Giuseppe
G
Mancuso
Giuseppe
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma