Rutgers School of Graduate Studies at The Health Sciences Campus, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Department of Pediatrics and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
mBio. 2018 Jan 9;9(1):e01828-17. doi: 10.1128/mBio.01828-17.
is the main etiologic agent of cryptococcal meningitis and causes a significant number of deadly infections per year. Although it is well appreciated that host immune responses are crucial for defense against cryptococcosis, our understanding of factors that control the development of effective immunity to this fungus remains incomplete. In previous studies, we identified the F-box protein Fbp1 as a novel determinant of virulence. In this study, we found that the hypovirulence of the Δ mutant is linked to the development of a robust host immune response. Infection with the Δ mutant induces a rapid influx of CCR2 monocytes and their differentiation into monocyte-derived dendritic cells (mo-DCs). Depletion of CCR2 monocytes and their derivative mo-DCs resulted in impaired activation of a protective inflammatory response and the rapid death of mice infected with the Δ mutant. Mice lacking B and T cells also developed fungal meningitis and succumbed to infection with the Δ mutant, demonstrating that adaptive immune responses to the Δ mutant help to maintain the long-term survival of the host. Adaptive immune responses to the Δ mutant were characterized by enhanced differentiation of Th1 and Th17 CD4 T cells together with diminished Th2 responses compared to the H99 parental strain. Importantly, we found that the enhanced immunogenicity of Δ mutant yeast cells can be harnessed to confer protection against a subsequent infection with the virulent H99 parental strain. Altogether, our findings suggest that Fbp1 functions as a novel virulence factor that shapes the immunogenicity of is the most common cause of deadly fungal meningitis, with over 270,000 infections per year. Immune responses are critically required for the prevention of cryptococcosis, and patients with impaired immunity and low CD4 T cell numbers are at high risk of developing these deadly infections. Although it is well appreciated that the development of protective immunity is shaped by the interactions of the host immune system with fungal cells, our understanding of fungal products that influence this process remains poor. In this study, we found that the activity of F-box protein 1 (Fbp1) in highly virulent clinical strain H99 shapes its immunogenicity and thus affects the development of protective immune responses in the host. The identification of this new mechanism of virulence may facilitate the future development of therapeutic interventions aimed at boosting antifungal host immunity.
是隐球菌性脑膜炎的主要病原体，每年导致大量致命感染。尽管人们充分认识到宿主免疫反应对于防御隐球菌病至关重要，但我们对控制宿主对这种真菌产生有效免疫的因素的理解仍然不完整。在之前的研究中，我们发现 F-box 蛋白 Fbp1 是一种新的毒力决定因素。在这项研究中，我们发现Δ突变体的低毒力与其宿主免疫反应的快速发展有关。感染Δ突变体导致 CCR2 单核细胞的快速流入和其分化为单核细胞衍生的树突状细胞（mo-DC）。CCR2 单核细胞及其衍生的 mo-DC 的耗竭导致保护性炎症反应的激活受损，感染Δ突变体的小鼠迅速死亡。缺乏 B 和 T 细胞的小鼠也发展为真菌性脑膜炎，并因感染Δ突变体而死亡，这表明宿主对Δ突变体的适应性免疫反应有助于维持其长期存活。与 H99 亲本株相比，宿主对Δ突变体的适应性免疫反应表现为 Th1 和 Th17 CD4 T 细胞的分化增强，而 Th2 反应减弱。重要的是，我们发现Δ突变体酵母细胞的增强免疫原性可以被利用来赋予对随后感染强毒力 H99 亲本株的保护。总之，我们的研究结果表明，Fbp1 作为一种新的毒力因子，塑造了隐球菌的免疫原性。是最常见的致命真菌性脑膜炎的病原体，每年有超过 27 万例感染。免疫反应对于预防隐球菌病至关重要，免疫功能受损和 CD4 T 细胞数量低的患者患这些致命感染的风险很高。尽管人们充分认识到保护性免疫的发展是由宿主免疫系统与真菌细胞的相互作用所塑造的，但我们对影响这一过程的真菌产物的了解仍然很差。在这项研究中，我们发现高度毒力的临床菌株 H99 中 F-box 蛋白 1 (Fbp1) 的活性塑造了其免疫原性，从而影响了宿主保护性免疫反应的发展。这种新的毒力机制的鉴定可能有助于未来开发旨在增强抗真菌宿主免疫的治疗干预措施。
