Exploring virulence and immunogenicity in the emerging pathogen Sporothrix brasiliensis
Exploring virulence and immunogenicity in the emerging pathogen Sporothrix brasiliensis
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DOI：
10.1371/journal.pntd.0005903
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发表时间：
2017-08-01
影响因子：
3.8
通讯作者：
de Camargo, Zoilo Pires
中科院分区：
文献类型：
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作者：
Della Terra, Paula Portella;Rodrigues, Anderson Messias;de Camargo, Zoilo Pires
孢子丝菌病是人类和动物的一种多态性慢性感染，通常是在受到孢子丝菌污染的土壤和植物材料的创伤性接种后获得的。繁殖体。另一种成功的传播途径是患病猫的咬伤和抓伤，通过这种途径，孢子丝酵母菌被接种到哺乳动物组织中。模拟替代传播途径的皮下孢子丝菌病小鼠模型的开发对于了解疾病发病机制和开发新的治疗策略至关重要。为了探讨动物中水平传播（例如猫猫）和人畜共患传播对孢子丝菌适应性的影响，BALB/c 小鼠的左后足垫接种了 5x10(6) 个酵母菌（n = 11 S. brasiliensis、n = 2 S. schenckii 或 n = 1 S. globosa）。感染后二十天，我们的模型再现了孢子丝菌病的病理生理学和症状学，其中化脓的皮下结节沿着淋巴管向近端进展。在申克链球菌分支的主要致病成员中，巴西链球菌通常比申克链球菌和球形链球菌的毒性更强。然而，巴西沙门氏菌的毒力依赖于菌株，我们证明高毒力分离株从左后足垫传播到受感染动物的肝脏、脾脏、肾脏、肺、心脏和大脑，导致显着的慢性体重减轻（体重减轻高达 15%）。感染后 2 至 16 周内，体重减轻与宿主死亡相关。组织病理学特征包括坏死、化脓性炎症以及多形核和单核炎症浸润。使用特异性抗血清和同源外抗原的免疫印迹研究了体液反应。抗原谱是分离株特异性的，支持这样的假设：随着时间的推移，不同的孢子丝菌种类可以引起异质的体液反应，但在巴西孢子丝菌和申克孢子丝菌蛋白质组之间观察到交叉反应。尽管免疫印迹谱存在很大差异，但在几乎 100% 的检测中，抗体主要源自针对 3-羧基-粘康酸环化酶、一种在 60 至 70 kDa (gp60-gp70) 之间振荡的糖蛋白和 100 kDa 分子。因此，我们的数据拓宽了当前对孢子丝菌-孢子丝菌病系统中毒力和免疫原性的看法，大大扩展了与具有不同毒力特征的分离株进行比较基因组的可能性，并有助于揭示支撑孢子丝菌毒力出现的分子机制和进化压力。
Sporotrichosis is a polymorphic chronic infection of humans and animals classically acquired after traumatic inoculation with soil and plant material contaminated with Sporothrix spp. propagules. An alternative and successful route of transmission is bites and scratches from diseased cats, through which Sporothrix yeasts are inoculated into mammalian tissue. The development of a murine model of subcutaneous sporotrichosis mimicking the alternative route of transmission is essential to understanding disease pathogenesis and the development of novel therapeutic strategies. To explore the impact of horizontal transmission in animals (e.g., cat-cat) and zoonotic transmission on Sporothrix fitness, the left hind footpads of BALB/c mice were inoculated with 5x10(6) yeasts (n = 11 S. brasiliensis, n = 2 S. schenckii, or n = 1 S. globosa). Twenty days post-infection, our model reproduced both the pathophysiology and symptomology of sporotrichosis with suppurating subcutaneous nodules that progressed proximally along lymphatic channels. Across the main pathogenic members of the S. schenckii clade, S. brasiliensis was usually more virulent than S. schenckii and S. globosa. However, the virulence in S. brasiliensis was strain-dependent, and we demonstrated that highly virulent isolates disseminate from the left hind footpad to the liver, spleen, kidneys, lungs, heart, and brain of infected animals, inducing significant and chronic weight loss (losing up to 15% of their body weight). The weight loss correlated with host death between 2 and 16 weeks post-infection. Histopathological features included necrosis, suppurative inflammation, and polymorphonuclear and mononuclear inflammatory infiltrates. Immunoblot using specific antisera and homologous exoantigen investigated the humoral response. Antigenic profiles were isolate-specific, supporting the hypothesis that different Sporothrix species can elicit a heterogeneous humoral response over time, but cross reaction was observed between S. brasiliensis and S. schenckii proteomes. Despite great diversity in the immunoblot profiles, antibodies were mainly derived against 3-carboxy-muconate cyclase, a glycoprotein oscillating between 60 and 70 kDa (gp60-gp70) and a 100-kDa molecule in nearly 100% of the assays. Thus, our data broaden the current view of virulence and immunogenicity in the Sporothrix-sporotrichosis system, substantially expanding the possibilities for comparative genomic with isolates bearing divergent virulence traits and helping uncover the molecular mechanisms and evolutionary pressures underpinning the emergence of Sporothrix virulence.