Uenotsuchi Takeshi, Takeuchi Satoshi, Matsuda Tetsuo, Urabe Kazunori, Koga Tetsuya, Uchi Hiroshi, Nakahara Takeshi, Fukagawa Shuji, Kawasaki Masako, Kajiwara Hideko, Yoshida Shin-Ichi, Moroi Yoichi, Furue Masutaka
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.
Int Immunol. 2006 Dec;18(12):1637-46. doi: 10.1093/intimm/dxl097. Epub 2006 Oct 11.
Sporotrichosis is caused by a thermo-dependent dimorphic fungus, Sporothrix schenckii. The major clinical manifestations occur in the skin; however, cases of visceral manifestations have also been increasingly reported with some being observed in immune compromised patients. Different virulence of individual S. schenckii strain as well as immune status of the host could contribute to form such different clinical manifestations. Thus, the purpose of the study was to investigate whether different virulence of individual S. schenckii could be a factor for such clinical difference. We investigated the interactions between human monocyte-derived dendritic cells (MoDCs) and S. schenckii, assessed by (i) morphological features, (ii) surface marker expressions, cytokine productions, (iii) signaling pathways and (iv) allostimulatory activity of the activated MoDCs. Immature MoDCs, obtained from peripheral blood monocytes supplemented with granulocyte macrophage colony-stimulating factor and IL-4, were stimulated with S. schenckii strains of both yeasts and conidia forms of different origins (cutaneous isolates: KMU4649, IFM5906 and IFM46010; visceral isolates: KMU4648, IFM41598 and ATCC26331) to be used for various assays. Through the analysis, we found that the cutaneous S. shenckii of cutaneous origins were more potent to activate MoDCs to induce strong T(h)1 response, as evidenced by abundant IFN-gamma production, while the S. shenckii of visceral origins induced only minimal dendritic cell activation and T(h)1 induction. The p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signaling pathways appeared to be associated with the differential activation of the MoDCs by S. schenckii of cutaneous and the visceral origins. Overall, we concluded that the differential activation of MoDCs by S. schenckii of cutaneous and visceral origins to induce T(h)1 response, other than immune status or the host, may be a factor for their different clinical manifestations.
孢子丝菌病由一种温度依赖性双相真菌申克孢子丝菌引起。主要临床表现出现在皮肤；然而，内脏表现的病例也越来越多地被报道，其中一些出现在免疫功能低下的患者中。申克孢子丝菌各个菌株的不同毒力以及宿主的免疫状态可能导致形成这些不同的临床表现。因此，本研究的目的是调查申克孢子丝菌各个菌株的不同毒力是否可能是造成这种临床差异的一个因素。我们研究了人单核细胞衍生树突状细胞（MoDCs）与申克孢子丝菌之间的相互作用，通过以下方面进行评估：（i）形态特征，（ii）表面标志物表达、细胞因子产生，（iii）信号通路，以及（iv）活化的MoDCs的同种异体刺激活性。从未成熟的MoDCs开始，这些细胞从补充了粒细胞巨噬细胞集落刺激因子和IL-4的外周血单核细胞中获得，用不同来源（皮肤分离株：KMU4649、IFM5906和IFM46010；内脏分离株：KMU4648、IFM41598和ATCC26331）的酵母和分生孢子形式的申克孢子丝菌菌株进行刺激，以用于各种检测。通过分析，我们发现皮肤来源的皮肤型申克孢子丝菌更能有效地激活MoDCs以诱导强烈的T(h)1反应，大量产生的IFN-γ证明了这一点，而内脏来源的申克孢子丝菌仅诱导最小程度的树突状细胞活化和T(h)1诱导。p38丝裂原活化蛋白激酶和c-Jun N末端激酶信号通路似乎与皮肤型和内脏型申克孢子丝菌对MoDCs的差异激活有关。总体而言，我们得出结论，皮肤型和内脏型申克孢子丝菌对MoDCs的差异激活以诱导T(h)1反应，而非免疫状态或宿主，可能是它们临床表现不同的一个因素。
