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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：
9919513
负责人：
Mairi C Noverr
金额：
$ 57.54万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919513
关键词：
Abdominal Infection Animal Model Anti-Inflammatory Agents Antibodies 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 Knockout Mice Lead Leukocytes Ligands 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 Induction Signal Transduction Staphylococcus aureus Suggestion Survivors Testing Therapeutic Therapeutic immunosuppression Training Vaccines Virulence Work adaptive immunity antimicrobial cell type clinically significant co-infection cytokine gene complementation in vivo inhibitor/antagonist interest macrophage microbial mortality novel pathogen pathogenic fungus polymicrobial sepsis programs public health relevance response secondary infection synergism

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袭性真菌感染的最常见原因通常源自胃肠道的生长和侵入。入侵最初会导致内部腹部感染 (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% 取决于患者的危险因素。我们最近开发了多种微生物的动物模型白色念珠菌 (Ca) 和金黄色葡萄球菌引起的真菌/细菌腹内感染 (IAI) (Sa) 模拟临床侵袭性疾病（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念珠菌 (Cd) 的共同感染导致死亡率<10%。特别令人感兴趣的是，Cd/Sa 或单独 Cd 的幸存者重新受到挑战致命的双重感染 (Ca/Sa) 导致存活率 >90%。保护反应持续长期（重新挑战前至少 60 天）且具有广谱性，提供保护对抗同样致命的热带念珠菌/Sa 和克柔念珠菌/Sa IAI。令人惊讶的是，Cd 诱导的对致命性 IAI 的保护不是由适应性免疫介导的，而是似乎是由通过训练有素的先天免疫机制（先天细胞介导的非特异性记忆）。初步数据表明，Cd 训练后的先天反应是由 Gr-1+ 骨髓细胞介导的衍生抑制细胞（MDSC）已在人类脓毒症中有报道。的概念由 MDSC 介导的训练有素的先天免疫对于传染病来说是新颖的。因此，我们的中心假设是，接触低毒力念珠菌物种会导致持续广泛的感染频谱训练的先天免疫保护可防止致命的多种微生物真菌-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重新介导的在训练先天免疫期间对 MDSC 进行编程。该提案的目标是定义宿主和微生物对诱导保护性训练的先天免疫的要求多种微生物败血症并研究诱导、训练和效应器涉及的机制功能。