Mechanisms of vaccine protection against AIDS-associated Cryptococcus infection

摘要 真菌感染往往是宿主死亡的一个未得到充分认识的致病原因。使用……的增加 在过去的几十年里，免疫抑制疗法导致了易感性的稳步增加。 世界各地的人口。此外，侵袭性真菌感染的死亡率仍然令人无法接受。 这是由于抗真菌药物经常无法有效控制真菌生长而导致的。目前没有真菌 疫苗即使作为宿主死亡率存在，也是由于包括烟曲霉(Af)在内的病原真菌， 新生隐球菌(CN)和加蒂隐球菌(CG)持续增加。因此，有一个明确的 医学上需要能够帮助保护易感人群的抗真菌疫苗。在以前的研究中，我们 确定CN-FBP1(HK-FBP1)突变酵母细胞的热灭活制剂可作为有效的 和新的候选疫苗。此外，我们最近发现，接种HK-FBP1疫苗可以 对不同真菌种类的交叉保护，包括烟曲霉、白色念珠菌和加蒂假丝酵母。这些发现 提示在HK-FBP1疫苗接种后，保守的抗真菌机制被激活，可以保护 对抗不同的真菌物种。在本附录中提出的研究中，我们试图扩展以下目标 父母拨款的重点是破译疫苗诱导的交叉保护Af的机制。我们 假设HK-FBP1疫苗通过激活训练有素的天然免疫来增强对Af的防御 细胞。先天免疫训练的概念已经成为一个日益增长和令人兴奋的研究领域。五花八门 研究支持这一观点，即宿主的感染史可以影响对暴露于随后的 感染。在之前的研究中，里维拉实验室证明，对房颤的防御依赖于髓系细胞 即使在没有整个淋巴间隔室的情况下也可以发生。因此，我们假设这部小说 HK-FBP1疫苗通过训练髓系细胞的免疫力来预防Af感染。我们会调查的 这一假说有以下几个独立的目的：1)破译HK-FBP1疫苗中先天细胞的作用。 诱导对真菌攻击的保护，以及2)确定干扰素信号在指导 抗真菌，肺内训练的先天细胞。这些拟议的研究将补充和扩大 家长拨款为HK-FBP1疫苗如何形成广泛保护性抗真菌提供新的见解 防守。这些研究将进一步推进泛真菌疫苗的研究。

ABSTRACT Fungal infections are often an under recognized pathogenic cause of host mortality. The rise in use of immunosuppressant therapeutics over the past decades has resulted in the steady increase of susceptible populations throughout the world. Moreover, mortality rates from invasive fungal infection remain unacceptably high due to the frequent inability of antifungal drugs to efficiently control fungal growth. Currently no fungal vaccines exist even as host mortality rates due to pathogenic fungi including Aspergillus fumigatus (Af), Cryptococcus neoformans (Cn), and Cryptococcus gatti (Cg), continue to increase. Therefore, there is a clear medical need for antifungal vaccines that can help protect susceptible populations. In previous studies we determined that heat-killed preparations of Cn-fbp1 (HK-Fbp1) mutant yeast cells can function as an effective and novel vaccine candidate. Furthermore, we recently uncovered that vaccination with HK-Fbp1 can confer cross-protection against different fungal species including A. fumigatus, C. albicans, and C. gatti. These findings suggest that upon HK-Fbp1 vaccination there is activation of conserved antifungal mechanisms that can protect against diverse fungal species. In the studies proposed in this supplement we seek to expand on the goals of the parental grant to focus on deciphering the mechanisms of vaccine-induced cross-protection against Af. We hypothesize that vaccination with HK-Fbp1 confers defense against Af via activation of trained innate immune cells. The concept of innate immune training has become a growing and exciting field of research. Various studies support the notion that the host’s history of infection can affect responses to exposure to subsequent infections. In previous studies the Rivera lab demonstrated that defense against Af is dependent on myeloid cells and can occur even in the absence of the entire lymphoid compartment. Thus, we hypothesize that this novel HK-Fbp1 vaccine confers protection against Af infection via trained immunity of myeloid cells. We will investigate this hypothesis via the following independent aims: 1) Decipher the roles of innate cells in HK-Fbp1, vaccine- induced protection against fungal challenges, and 2) Define the role of IFN signaling in the instruction of antifungal, pulmonary trained innate cells. These proposed studies will complement and expand the scope of the parental grant to provide novel insight on how HK-Fbp1 vaccine shapes broadly protective antifungal defense. These studies will further advance the search for a pan-fungal vaccine.