Siqueira Isaque Medeiros, de Castro Raffael Júnio Araújo, Leonhardt Luiza Chaves de Miranda, Jerônimo Márcio Sousa, Soares Aluízio Carlos, Raiol Tainá, Nishibe Christiane, Almeida Nalvo, Tavares Aldo Henrique, Hoffmann Christian, Bocca Anamelia Lorenzetti
Molecular Pathology Post-Graduate Program, School of Medicine; University of Brasília, Brasília, Brazil.
Department of Cell Biology, Institute of Biological Sciences; University of Brasília, Brasília, Brazil.
PLoS Negl Trop Dis. 2017 Mar 29;11(3):e0005461. doi: 10.1371/journal.pntd.0005461. eCollection 2017 Mar.
A common theme across multiple fungal pathogens is their ability to impair the establishment of a protective immune response. Although early inflammation is beneficial in containing the infection, an uncontrolled inflammatory response is detrimental and may eventually oppose disease eradication. Chromoblastomycosis (CBM), a cutaneous and subcutaneous mycosis, caused by dematiaceous fungi, is capable of inducing a chronic inflammatory response. Muriform cells, the parasitic form of Fonsecaea pedrosoi, are highly prevalent in infected tissues, especially in long-standing lesions. In this study we show that hyphae and muriform cells are able to establish a murine CBM with skin lesions and histopathological aspects similar to that found in humans, with muriform cells being the most persistent fungal form, whereas mice infected with conidia do not reach the chronic phase of the disease. Moreover, in injured tissue the presence of hyphae and especially muriform cells, but not conidia, is correlated with intense production of pro-inflammatory cytokines in vivo. High-throughput RNA sequencing analysis (RNA-Seq) performed at early time points showed a strong up-regulation of genes related to fungal recognition, cell migration, inflammation, apoptosis and phagocytosis in macrophages exposed in vitro to muriform cells, but not conidia. We also demonstrate that only muriform cells required FcγR and Dectin-1 recognition to be internalized in vitro, and this is the main fungal form responsible for the intense inflammatory pattern observed in CBM, clarifying the chronic inflammatory reaction observed in most patients. Furthermore, our findings reveal two different fungal-host interaction strategies according to fungal morphotype, highlighting fungal dimorphism as an important key in understanding the bipolar nature of inflammatory response in fungal infections.
多种真菌病原体的一个共同特点是它们能够破坏保护性免疫反应的建立。虽然早期炎症有助于控制感染，但不受控制的炎症反应是有害的，最终可能阻碍疾病的根除。着色芽生菌病（CBM）是一种由暗色真菌引起的皮肤和皮下真菌病，能够诱导慢性炎症反应。链状细胞，即裴氏瓶霉的寄生形式，在感染组织中高度普遍，尤其是在长期病变中。在本研究中，我们表明菌丝和链状细胞能够引发具有与人类相似的皮肤病变和组织病理学特征的小鼠CBM，链状细胞是最持久的真菌形式，而感染分生孢子的小鼠不会进入疾病的慢性期。此外，在受损组织中，菌丝尤其是链状细胞的存在，而非分生孢子，与体内促炎细胞因子的大量产生相关。在早期时间点进行的高通量RNA测序分析（RNA-Seq）显示，体外暴露于链状细胞而非分生孢子的巨噬细胞中，与真菌识别、细胞迁移、炎症、凋亡和吞噬作用相关的基因强烈上调。我们还证明，只有链状细胞在体外内化需要FcγR和Dectin-1识别，这是CBM中观察到的强烈炎症模式的主要真菌形式，阐明了大多数患者中观察到的慢性炎症反应。此外，我们的研究结果揭示了根据真菌形态型的两种不同的真菌-宿主相互作用策略，突出了真菌二态性是理解真菌感染中炎症反应两极性质的重要关键。
