Candida mediated protection against polymicrobial sepsis

项目说明 真菌病原体白色念珠菌是侵袭性真菌感染的最常见原因 通常起源于胃肠道的生长和侵袭。入侵最初会导致内部- 腹部感染(IAI)，通常是多菌的，可导致血液感染 和致命的败血症。当涉及真菌种类时，死亡率急剧增加到50%- 75%取决于患者的风险因素。我们最近开发了一种多菌素的动物模型 白色念珠菌和金黄色葡萄球菌腹内真菌/细菌感染 (Sa)模仿临床侵袭性疾病(传播/败血症)，导致80%-100%的死亡 接种后96h内。相比之下，与密切相关的都柏林弧菌(CD)合并感染 导致10%的死亡率。特别令人感兴趣的是，CD/SA或CD的幸存者再次受到挑战 致命的混合感染(Ca/Sa)导致90%的存活率。保护性反应是持续的 长期(至少在重新挑战前60天内)，并提供广泛的保护 对同样致死的热带锥虫/Sa和克氏锥虫/Sa ai。令人惊讶的是，Cd诱导的 对致命性IAI的保护并不是由获得性免疫介导的，相反，似乎是 通过一种经过训练的先天免疫机制(由先天细胞调节的非特定记忆)。 初步数据表明，CD的训练性先天反应是由Gr-1+髓系细胞介导的 已在人类败血症中报道的衍生抑制细胞(MDSC)。这一概念 MDSCs介导的训练性先天免疫是治疗传染病的新方法。因此，我们的 中心假说是接触低毒力的念珠菌会导致持续的广泛 光谱训练的先天免疫保护，防止致命的多菌真菌-细菌败血症。 从机制上讲，我们假设保护性反应是由表观遗传的Re-Re介导的。 在训练的先天免疫力期间编程的MDSCs。这项提案的目标是界定 诱导保护性训练先天免疫的寄主和微生物需求 多菌败血症及其诱导、训练和效应机制的研究 功能。

Project Description The fungal pathogen Candida albicans is the most common cause of invasive fungal infection often originating from outgrowth and invasion from the GI tract. Invasion initially causes intra- abdominal infections (IAI), which are often polymicrobial, and can lead to bloodstream infection and fatal sepsis. When fungal species are involved, mortality rates increase dramatically to 50- 75% depending on patient risk factors. We recently developed an animal model of polymicrobial fungal/bacterial intra-abdominal infection (IAI) with C. albicans (Ca) and Staphylococcus aureus (Sa) that mimics clinical invasive disease (dissemination/sepsis) resulting in 80-100% mortality within 96 h post-inoculation. In contrast, co-infection with the closely related C. dubliniensis (Cd) resulted in <10% mortality. Of particular interest, survivors of Cd/Sa or Cd alone re-challenged with a lethal co-infection (Ca/Sa) resulted in >90% survival. The protective response is sustained long term (up to at least 60 days prior to re-challenge) and is broad-spectrum providing protection against similarly lethal C. tropicalis/Sa and C. krusei/Sa IAI. Surprisingly, the Cd-induced protection against lethal IAI is NOT mediated by adaptive immunity, but instead appears to be through a mechanism of trained innate immunity (non-specific memory mediated by innate cells). Preliminary data indicate that the trained innate response by Cd is mediated by Gr-1+ myeloid derived suppressor cells (MDSC) that have been reported in human sepsis. The concept of trained innate immunity mediated by MDSCs is novel for infectious disease. Accordingly, our central hypothesis is that exposure to low virulence Candida species induce sustained broad spectrum trained innate immune protection against lethal polymicrobial fungal-bacterial sepsis. Mechanistically, we hypothesize that the protective response is mediated by epigenetically re- programed MDSCs during trained innate immunity. The objective of this proposal is to define host and microbial requirements for induction of protective trained innate immunity during polymicrobial sepsis and investigate mechanisms involved in induction, training and effector functions.