Indoleamine 2,3-dioxygenase controls fungal loads and immunity in Paracoccidioidomicosis but is more important to susceptible than resistant hosts.
Indoleamine 2,3-dioxygenase controls fungal loads and immunity in Paracoccidioidomicosis but is more important to susceptible than resistant hosts.
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DOI：
10.1371/journal.pntd.0003330
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发表时间：
2014-11
影响因子：
3.8
通讯作者：
Calich VL
中科院分区：
文献类型：
--
作者：
Araújo EF;Loures FV;Bazan SB;Feriotti C;Pina A;Schanoski AS;Costa TA;Calich VL
副球孢子菌病是一种仅限于拉丁美洲的原发性真菌感染，是通过吸入真菌颗粒而获得的。控制严重和轻度副球孢子菌病的免疫调节机制仍不清楚。吲哚胺 2,3-双加氧酶 (IDO) 是一种 IFN-γ 诱导酶，可催化色氨酸代谢，可通过抑制病原体生长、T 细胞免疫和组织炎症来控制宿主与病原体的相互作用。在这项研究中，我们研究了 IDO 在易感和耐药小鼠肺副球孢子菌病中的作用。 IDO 被 1-甲基-dl-色氨酸 (1MT) 阻断，并在体外和体内研究了真菌感染。 1MT处理的耐药小鼠和易感小鼠的巨噬细胞中，巴西副球孢子菌感染比未处理的巨噬细胞更严重，同时犬尿氨酸和IDO mRNA的产生减少。在肺部感染中也观察到类似的结果。与宿主遗传模式无关，IDO 抑制降低了真菌清除率，但增强了 T 细胞免疫力。早期 IDO 抑制导致树突状细胞和 Th17 细胞分化增加，同时 Th1 和 Treg 细胞反应减弱。尽管有这些相同的生物效应，但仅在易感小鼠中，暂时的 IDO 阻断会导致真菌持续生长、组织病理学增加和死亡率增加。相比之下，耐药小鼠能够通过后期控制真菌负荷来恢复短暂的 IDO 封锁，而无需增强组织病理学。我们的研究首次证明，在肺副球孢子菌病中，IDO 是一种重要的免疫调节酶，可促进真菌清除并抑制 T 细胞免疫和炎症，对易感宿主具有突出的重要性。事实上，只有在易受影响的背景下，IDO 抑制才会导致不受控制的组织病理学和死亡率。我们的研究结果为理解副球孢子菌病的免疫病理学开辟了新的视角，并表明 IDO 活性不足可能与以真菌清除效率低下和过度炎症为特征的人类 PCM 严重病例有关。副球孢子菌病是拉丁美洲流行的一种系统性真菌病，其免疫保护是由 T 细胞免疫介导的，而免疫抑制则是该疾病严重形式的特征。吲哚胺 2,3-双加氧酶 (IDO) 是一种主要由 IFN-γ 诱导的酶，沿着犬尿氨酸途径分解色氨酸。色氨酸缺乏与病原体生长减少有关，而犬尿氨酸水平升高会抑制免疫反应。在本研究中，使用耐药和易感小鼠研究了 IDO 在肺副球孢子菌病中的作用。在这两种小鼠品系中，1-甲基色氨酸阻断 IDO 会导致真菌清除效率低下，同时 T 细胞免疫力也会增强。尽管有这些相同的生物效应，但仅在易感小鼠中，IDO 抑制会导致进行性真菌生长和组织病理学，从而导致死亡率增加。我们的研究结果首次证明，IDO 在肺副球孢子菌病中发挥着尚未探索的免疫调节作用，这在该疾病的严重病例中尤其重要。
Paracoccidioidomycosis, a primary fungal infection restricted to Latin America, is acquired by inhalation of fungal particles. The immunoregulatory mechanisms that control the severe and mild forms of paracoccidioidomycosis are still unclear. Indoleamine 2,3-dioxygenase (IDO), an IFN-γ induced enzyme that catalyzes tryptophan metabolism, can control host-pathogen interaction by inhibiting pathogen growth, T cell immunity and tissue inflammation. In this study, we investigated the role of IDO in pulmonary paracoccidioidomycosis of susceptible and resistant mice. IDO was blocked by 1-methyl-dl-tryptophan (1MT), and fungal infection studied in vitro and in vivo. Paracoccidioides brasiliensis infection was more severe in 1MT treated than untreated macrophages of resistant and susceptible mice, concurrently with decreased production of kynurenines and IDO mRNA. Similar results were observed in the pulmonary infection. Independent of the host genetic pattern, IDO inhibition reduced fungal clearance but enhanced T cell immunity. The early IDO inhibition resulted in increased differentiation of dendritic and Th17 cells, accompanied by reduced responses of Th1 and Treg cells. Despite these equivalent biological effects, only in susceptible mice the temporary IDO blockade caused sustained fungal growth, increased tissue pathology and mortality rates. In contrast, resistant mice were able to recover the transitory IDO blockade by the late control of fungal burdens without enhanced tissue pathology. Our studies demonstrate for the first time that in pulmonary paracoccidioidomycosis, IDO is an important immunoregulatory enzyme that promotes fungal clearance and inhibits T cell immunity and inflammation, with prominent importance to susceptible hosts. In fact, only in the susceptible background IDO inhibition resulted in uncontrolled tissue pathology and mortality rates. Our findings open new perspectives to understand the immunopathology of paracoccidioidomycosis, and suggest that an insufficient IDO activity could be associated with the severe cases of human PCM characterized by inefficient fungal clearance and excessive inflammation. Immunoprotection to paracoccidiodomycosis, a systemic mycosis endemic in Latin America, is mediated by T cell immunity whereas immunosuppression characterizes the severe forms of the disease. Indoleamine 2,3-dioxygenase (IDO), an enzyme mainly induced by IFN-γ, catabolizes tryptophan along the kynurenines pathway. Tryptophan deficiency has been associated with reduced pathogen growth, while elevated levels of kynurenines with suppressed immune responses. In this study, the role of IDO in pulmonary paracoccidioidomycosis was investigated using resistant and susceptible mice. In both mouse strains, IDO blockade by 1-methyl tryptophan resulted in inefficient fungal clearance accompanied by enhanced T cell immunity. Despite these equivalent biological effects, only in susceptible mice IDO inhibition caused progressive fungal growth and tissue pathology resulting in increased mortality. Our findings demonstrate for the first time that IDO exert a yet unexplored immunoregulatory role in pulmonary paracoccidioidomycosis that can be particularly important in the severe cases of the disease.
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影响因子：
3.7
作者：
Felonato, Maira;Pina, Adriana;Calich, Vera L. G.
通讯作者：
Calich, Vera L. G.
影响因子：
4.6
作者：
Corvino, C. L.;Mamoni, R. L.;Blotta, M. H. S. L.
通讯作者：
Blotta, M. H. S. L.
影响因子：
4.4
作者：
Bozza, Silvia;Zelante, Teresa;Romani, Luigina
通讯作者：
Romani, Luigina
影响因子：
3.1
作者：
Cano, LE;Singer-Vermes, LM;Calich, VLG
通讯作者：
Calich, VLG
影响因子：
5.8
作者：
Arruda, Celina;Vaz, Celideia A. C.;Calich, Vera L. G.
通讯作者：
Calich, Vera L. G.