Molecular Pathology Post-Graduate Program, School of Medicine, University of Brasília, Brasília, Brazil.
Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, United States of America.
PLoS Negl Trop Dis. 2020 Jun 15;14(6):e0008386. doi: 10.1371/journal.pntd.0008386. eCollection 2020 Jun.
Chromoblastomycosis (CBM) is a chronic worldwide subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. It is difficult to treat patients with the disease, mainly because of its recalcitrant nature. The correct activation of host immune response is critical to avoid fungal persistence in the tissue and disease chronification. CD4+ T cells are crucial for the development of protective immunity to F. pedrosoi infection. Here, we investigated T helper cell response dynamics during experimental CBM. Following footpad injection with F. pedrosoi hyphae and conidia, T cells were skewed towards a Th17 and Th1 phenotype. The Th17 population was the main Th cell subset found in the infected area during the early stages of experimental murine CBM, followed by Th1 predominance in the later stages, coinciding with the remission phase of the disease in this experimental model. Depletion of CD25+ cells, which leads to a reduction of Treg cells in the draining lymph node, resulted in decline in fungal burden after 14 days of infection. However, fungal cells were not cleared in the later stages of the disease, prolonging CBM clinical features in those animals. IL-17A and IFN-γ neutralization hindered fungal cell elimination in the course of the disease. Similarly, in dectin-2 KO animals, Th17 contraction in the course of experimental CBM was accompanied by fungal burden decrease in the first 14 days of infection, although it did not affect disease resolution. In this study, we gained insight into T helper subsets' dynamics following footpad injections of F. pedrosoi propagules and uncovered their contribution to disease resolution. The Th17 population proved to be important in eliminating fungal cells in the early stages of infection. The Th1 population, in turn, closely assisted by Treg cells, proved to be relevant not only in the elimination of fungal cells at the beginning of infection but also essential for their complete elimination in later stages of the disease in a mouse experimental model of CBM.
着色芽生菌病（CBM）是一种慢性、世界性的皮下真菌感染，由几种二相性、色素性暗色真菌引起。治疗该病患者较为困难，主要是因为其具有难治性。正确激活宿主免疫反应对于避免真菌在组织中持续存在和疾病慢性化至关重要。CD4+T 细胞对于对抗 F. pedrosoi 感染的保护性免疫的发展至关重要。在这里，我们研究了实验性 CBM 中 T 辅助细胞反应的动态变化。在脚部注射 F. pedrosoi 菌丝和孢子后，T 细胞向 Th17 和 Th1 表型倾斜。在实验性 CBM 的早期阶段，Th17 群体是感染区域中主要的 Th 细胞亚群，随后在后期阶段 Th1 占主导地位，这与该实验模型中疾病的缓解阶段相吻合。耗尽 CD25+细胞（导致引流淋巴结中的 Treg 细胞减少）导致感染后 14 天真菌负荷下降。然而，在疾病的后期阶段，真菌细胞并未被清除，导致这些动物的 CBM 临床特征延长。IL-17A 和 IFN-γ 的中和作用阻碍了疾病过程中真菌细胞的清除。同样，在 dectin-2 KO 动物中，实验性 CBM 过程中 Th17 的收缩伴随着感染后前 14 天真菌负荷的减少，尽管它不影响疾病的解决。在这项研究中，我们深入了解了 F. pedrosoi 繁殖体脚部注射后 T 辅助亚群的动态变化，并揭示了它们对疾病缓解的贡献。Th17 群体在感染早期消除真菌细胞方面发挥了重要作用。而 Th1 群体，在 Treg 细胞的密切协助下，不仅在感染初期消除真菌细胞方面具有重要意义，而且对于在 CBM 小鼠实验模型中疾病后期的完全消除也至关重要。
