IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis.
IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis.
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IL-22和IDO1影响对鼠和人类阴道念珠菌病的免疫和耐受性。
DOI：
10.1371/journal.ppat.1003486
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Romani L
中科院分区：
文献类型：
--
作者：
De Luca A;Carvalho A;Cunha C;Iannitti RG;Pitzurra L;Giovannini G;Mencacci A;Bartolommei L;Moretti S;Massi-Benedetti C;Fuchs D;De Bernardis F;Puccetti P;Romani L
耐受白色念珠菌（胃肠道和阴道的人类寄生虫）的能力暗示宿主抵抗和耐受的防御机制合作以限制不同身体部位的真菌负荷和炎症。我们评估了实验性和人类外阴阴道念珠菌病（VVC）以及复发性VVC（RVVC）对真菌的耐药性和耐受性。在小鼠VVC中，分别涉及产生IL-22和IL-10的调节性T细胞的抵抗和耐受机制都被激活，其中吲哚胺2，3-双加氧酶1（IDO 1）的贡献最大。IDO 1负责产生致耐受性犬尿氨酸，使得用犬尿氨酸的替代疗法恢复对VVC的免疫保护。在人类中，发现IL 22和IDO 1基因中的两种功能性遗传变异与对RVVC的抗性增强相关，并且它们与IL-22、IDO 1和犬尿氨酸的局部表达增加相关。因此，IL-22和IDO 1在平衡念珠菌耐药性和耐受性方面至关重要，它们的缺陷是RVVC的风险因素，通过治疗性犬尿氨酸靶向耐受性可能使RVVC患者受益。这项研究解开了小鼠和人类C。白色念珠菌阴道感染，并引入了具有挑战性的概念的疾病，由于有缺陷的耐受机制。外阴阴道念珠菌病（VVC）和复发性VVC（RVVC）是影响大量健康女性的两种疾病。简单的VVC与几个诱发因素有关，而RVVC，以特发性复发发作为标志，可能实际上是无法治疗的。尽管公认的风险因素越来越多，但需要进一步了解阴道中的抗念珠菌宿主防御机制，以优化疫苗开发和免疫干预，以整合甚至取代抗真菌治疗。事实上，增加宿主耐药性的药物治疗，如抗真菌药，对个体症状发作非常有效，但不能防止复发，而且人们担心重复治疗可能会诱导耐药性。由于耐受机制预期不会对病原体产生相同的选择性压力，因此靶向耐受的新药将提供治疗方法，使低毒力病原体，如C。白色念珠菌不会产生耐药性。本研究提供了一个概念验证，即通过治疗性犬尿氨酸靶向耐受可能使RVVC患者受益。
The ability to tolerate Candida albicans, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in IL22 and IDO1 genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC. This study disentangles resistance and tolerance components of murine and human C. albicans vaginal infection and introduces the challenging notion of a disease due to a defective tolerance mechanism. Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) are two forms of disease that affect a large number of otherwise healthy women. Uncomplicated VVC is associated with several predisposing factors, whereas RVVC, marked by idiopathic recurrent episodes, may be virtually untreatable. Despite a growing list of recognized risk factors, further understanding of anti-Candida host defense mechanisms in the vagina is needed to optimize vaccine development and immune interventions to integrate with, or even replace, antifungal therapy. Indeed, medical treatments that increase host resistance, such as antifungals, are highly effective for individual symptomatic attacks but do not prevent recurrences and there is concern that repeated treatments might induce drug resistance. As tolerance mechanisms are not expected to have the same selective pressure on pathogens, new drugs that target tolerance will provide therapies to which low-virulence pathogens, such as C. albicans, will not develop resistance. This study provides a proof-of-concept that targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.
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影响因子：
11.8
作者：
Babula, O;Lazdane, G;Witkin, SS
通讯作者：
Witkin, SS
影响因子：
3.1
作者：
Gessner, Melissa A.;Werner, Jessica L.;Steele, Chad
通讯作者：
Steele, Chad
影响因子：
3.1
作者：
FIDEL, PL;LYNCH, ME;SOBEL, JD
通讯作者：
SOBEL, JD
DOI：
10.1369/jhc.2009.953604
发表时间：
2010-01-01
期刊：
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
影响因子：
--
作者：
Dai, Xiangchen;Zhu, Bao Ting
通讯作者：
Zhu, Bao Ting
影响因子：
2.9
作者：
Fidel, PL;Barousse, M;Dunlap, K
通讯作者：
Dunlap, K