Candida mediated protection against polymicrobial sepsis

念珠菌介导的针对多种微生物败血症的保护作用

基本信息

批准号：
10583504
负责人：
PAUL L FIDEL
金额：
$ 57.58万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-22 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583504
关键词：
Abdominal Infection Animal Model Anti-Inflammatory Agents Antibodies Bacteremia Candida Candida albicans Cells Clinical Communicable Diseases Data Dinoprostone Disease Epigenetic Process Exposure to Gastrointestinal tract structure Gene Expression Human Immune Immunity Infection Intra-abdominal Invaded Knockout Mice Leukocytes Ligands Macrophage Mediating Memory Methods Modification Morphogenesis Mus Mycoses Myeloid-derived suppressor cells Natural Immunity Organism Pathway interactions Patient risk Phenotype Reporting Risk Factors Role S100A9 gene Secondary to Sepsis Signal Transduction Staphylococcus aureus Survivors Testing Therapeutic immunosuppression Training Virulence Work adaptive immunity antimicrobial cell type clinically significant co-infection cytokine gene complementation in vivo inhibitor interest microbial mortality novel pathogen pathogenic fungus polymicrobial sepsis public health relevance response secondary infection synergism translational therapeutics vaccine access

项目摘要

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.

项目描述真菌病原体白色念珠菌是侵入性真菌感染的最常见原因通常起源于胃肠道的出生和入侵。入侵最初会导致内部腹部感染（IAI），通常是多细胞性的，可能导致血液感染和致命的败血症。当涉及真菌物种时，死亡率急剧增加到50-- 75％取决于患者的危险因素。我们最近开发了一种多数菌的动物模型真菌/细菌性腹腔内感染（IAI），白色念珠菌（CA）和金黄色葡萄球菌（SA）模仿临床侵入性疾病（传播/败血症），导致80-100％死亡率接种后96小时内。相反，与密切相关的都柏林梭菌（CD）共同感染导致<10％的死亡率。特别感兴趣的是，CD/SA或CD的幸存者仅重新挑战致命的共感染（CA/SA）导致> 90％的存活率。保护性反应持续长期（至少在重新挑战之前至少60天），并且提供保护针对同样致命的C. tropicalis/sa和C. krusei/sa iai。令人惊讶的是，CD引起的防止致命IAI的保护不是由适应性免疫来介导的，而是似乎是通过训练有素的先天免疫（由先天细胞介导的非特异性记忆）的机制。初步数据表明，CD训练的先天反应是由GR-1+髓样介导的在人类败血症中报道的衍生抑制细胞（MDSC）。概念由MDSC介导的训练有素的先天免疫是用于传染病的新颖。因此，我们的中心假设是暴露于低毒力念珠菌物种会诱导持续广泛谱系训练有素的先天免疫保护，以防止致命性多数真菌 - 细菌败血症。从机械上讲，我们假设保护反应是由表观遗传重新遗传的在训练有素的先天免疫力期间，编程了MDSC。该提议的目的是定义宿主和微生物要求在诱导保护性训练的先天免疫多数型败血症并研究涉及诱导，训练和效应子的机制功能。