Cryptococcus neoformans is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How Cryptococcus is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes Cryptococcus virulence by regulating host-Cryptococcus interactions. Our recent studies demonstrated that the fbp1Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed fbp1Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed fbp1Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed fbp1Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including C. neoformans, C. gattii, and Aspergillus fumigatus, as well as partial protection against Candida albicans Thus, our data suggest that the heat-killed fbp1Δ strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations.IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans, elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.

中文翻译：

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热杀死隐球菌突变株诱导宿主对小鼠疫苗模型中的多种侵袭性真菌病的保护。

新型隐球菌是一种真菌病原体，会感染肺部，然后通常扩散到中枢神经系统，引起脑膜炎。隐球菌如何能够抑制宿主免疫力并逃脱巨噬细胞的抗真菌活性仍未完全了解。我们报道，F盒蛋白Fbp1，SCF（Fbp1）E3连接酶的一个亚基，通过调节宿主-隐球菌的相互作用来促进隐球菌的毒力。我们最近的研究表明，fbp1Δ突变体在肺部引发了优越的保护性Th1宿主免疫力，并且可以利用热灭活的fbp1Δ酵母细胞增强的免疫原性来提供保护，以防止随后被强毒的亲本菌株感染。因此，我们研究了在几种疫苗接种策略中使用热杀死的fbp1Δ细胞。有趣的是 即使在耗尽CD4 + T细胞的小鼠中，疫苗保护仍然有效。在艾滋病毒/艾滋病引起的免疫缺陷的情况下，这一发现特别重要。此外，我们观察到，用热灭活的fbp1Δ进行免疫的小鼠可诱导针对多种侵袭性真菌病原体（包括新孢梭菌，加迪梭菌和烟曲霉）的攻击具有显着的交叉保护作用，以及针对白色念珠菌的部分保护作用。因此，我们的数据提示热灭活的fbp1Δ菌株有潜力成为抵抗隐球菌病和免疫侵害和免疫受损人群中隐球菌和其他侵袭性真菌感染的合适疫苗。在临床上没有可用于预防和控制真菌感染的疫苗。我们最近的研究表明，F-box蛋白Fbp1的突变体，即新隐球菌中SCF（Fbp1）E3连接酶的一个亚基，引起了较高的Th1宿主保护性免疫力。在这里，我们证明了热灭活的fbp1Δ细胞（HK-fbp1）可以被利用来赋予保护性以抵抗强毒的亲本菌株的攻击，即使是在CD4 + T细胞耗尽的动物中也是如此。在艾滋病毒/艾滋病引起的免疫缺陷的情况下，这一发现特别重要。此外，我们观察到HK-fbp1疫苗诱导了针对各种侵袭性真菌病原体的攻击的显着交叉保护。从而，