Stimulation via Toll-like receptor 9 reduces Cryptococcus neoformans-induced pulmonary inflammation in an IL-12-dependent manner

被引:43
作者
Edwards, L
Williams, AE
Krieg, AM
Rae, AJ
Snelgrove, RJ
Hussell, T [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Dept Biol Sci, CMMI, London SW7 2AZ, England
[2] Coley Pharmaceut Grp, Wellesley, MA USA
基金
英国医学研究理事会;
关键词
toll receptors; fungal infection; lung; inflammation; Eosinophilia;
D O I
10.1002/eji.200425640
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Cytosine-phosphate-guanosine-containing oligodeoxynucleotides (CpG ODN) are important vaccine adjuvants that promote Th1-type immune responses. Cryptococcus neoformans is a serious human pathogen that replicates in the lung but may disseminate systemically leading to meningitis, particularly in immunocompromised individuals. Immunization of susceptible C57BL/6 mice with CpG ODN deviates the immune response from a Th2- toward a Th1-type response following infection with C neoformans. CpG also induces IL-12, TNF, MCP-1 and macrophage nitric oxide production. CD4(+) and CD8(+) T cells producing IFN-gamma increase in frequency, while those producing IL-5 decrease. More importantly, pulmonary eosinophilia is significantly reduced, an effect that depends on IL-12 and CD8(+) T cells but not NK cells. CpG treatment also reduces the burden of C. neoformans in the lung, an effect that is IL-12-, NK cell- and T cell-independent and probably reflects a direct effect of CpG on pathogen opsonization or an enhancement of macrophage antimicrobial activity. An equivalent beneficial effect is also observed when CpG ODN treatment is delivered during established cryptococcal. disease. This is the first study documenting that promotion of lung TLR9 signaling using synthetic agonists enhances host defense. Activation of innate immunity has clear therapeutic potential and may even be beneficial in patients with acquired immune deficiency.
引用
收藏
页码:273 / 281
页数:9
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