Candida mediated protection against polymicrobial sepsis

项目描述 真菌病原体白色念珠菌是侵袭性真菌感染的最常见原因 通常起源于从胃肠道的生长和侵入。入侵最初导致内部- 腹部感染（IAI），通常是多种微生物，可导致血流感染 和致命的败血症当涉及真菌物种时，死亡率急剧增加至50- 75%取决于患者的风险因素。我们最近开发了一种多微生物的动物模型， 真菌/细菌腹腔感染（IAI），C.白色念珠菌（Ca）和金黄色葡萄球菌 (Sa)与临床侵袭性疾病（播散/败血症）相似，导致80-100%死亡率 接种后96 h内。与此相反，与密切相关的C.都柏林菌（Cd） 死亡率<10%。特别值得注意的是，Cd/Sa或单独Cd的存活者再次激发 致死性共感染（Ca/Sa）导致>90%的存活。保护性反应持续 长期（再激发前至少60天），具有广谱保护作用 对抗同样致命的C. tropicalis/Sa和C. krusei/Sa IAI.令人惊讶的是，镉诱导的 对致死性IAI的保护作用不是由适应性免疫介导的，而是由 通过训练的先天免疫机制（由先天细胞介导的非特异性记忆）。 初步数据表明，镉诱导的先天性反应是由Gr-1+髓样细胞介导的。 衍生的抑制细胞（MDSC），已报告在人类败血症。的概念 由MDSC介导的训练的先天免疫对于感染性疾病是新颖的。因此，我们 中心假设是暴露于低毒力念珠菌属物种诱导持续广泛的 频谱训练的先天免疫保护，对致命的多微生物真菌-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学上的再- 在训练的先天免疫期间编程MDSC。本提案的目的是确定 宿主和微生物对诱导保护性训练的先天免疫的要求 多微生物脓毒症和研究机制参与诱导，训练和效应 功能协调发展的

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.