NEONATAL CANDIDIASIS & IMMUNE COMPROMISE DURING DEVELOPMENT

新生儿念珠菌病

• 批准号: 8360538
• 负责人: Joseph Mark Bliss
• 金额: $ 17.57万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360538
• 关键词: AIDS/HIV problem; Adult; Antifungal Agents; Antigens; Biology; Birth; Blood; Burn injury; Candida; Candida albicans; Candidiasis; Cellular Immunity; Centers of Research Excellence; Child; Communicable Diseases; Development; Disease; Effector Cell; Environment; Equilibrium; Funding; Genes; Grant; Growth; Host Defense; Human; Humoral Immunities; Hyphae; Immune; Immune system; Immunity; Immunoglobulin Fragments; Immunoglobulin G; Impairment; Infant; Infection; Infectious Agent; Integration Host Factors; Lead; Life; Malignant Neoplasms; Microarray Analysis; Microbe; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Morphology; Mus; National Center for Research Resources; Neonatal; Organ; Organism; Patients; Perinatal; Phenotype; Physiological; Population; Predisposition; Premature Infant; Principal Investigator; Research; Research Infrastructure; Resources; Role; Screening procedure; Solid; Source; System; Testing; United States National Institutes of Health; Virulence; cDNA Library; cost; design; environmental change; fetal; fungus; high risk infant; improved; mortality; mutant; neonate; neutrophil; pathogen; premature; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Conditions leading to immune compromise in the host shift the balance between host and pathogen, making certain populations particularly susceptible to infectious diseases with accelerated rates of mortality and morbidity. The neonate is one such host. The protective intrauterine environment makes a robust immune defense unnecessary. However, the dramatic physiologic and environmental changes that occur at birth require adaptation in every fetal system, including immunity. Although even the full term infant requires months to fully develop the robust host defenses of older children, the preterm infant has additional challenges. These infants are vulnerable to infection due to impairment in both humoral and cellular immunity. Importantly, similar vulnerabilities are seen in some adult populations as well. Immune compromise occurs in such diverse settings as blood and solid organ malignancies, HIV/AIDS, and burn patients. Therefore, we believe that identification of the host factors in the premature neonate contributing to its susceptibility to infection will also inform the mechanisms of vulnerability in other immune compromised populations. We have generated and characterized monoclonal antibody fragments specific to the hyphae of C. albicans, a growth morphology associated with virulence. Specific Aim 1 will further define the hyphal antigens that are recognized by these antibody fragments through cDNA library screening. We will also examine the role of these antigens in virulence of the organism by constructing mutants for these genes and examining their phenotype in a murine neonatal model of candidiasis. Specific Aim 2 will express these antibody fragments in the context of bonafide human IgG and test these monoclonal antibodies for their ability to be protective against disseminated disease in the neonatal candidiasis model. Specific Aim 3 will take advantage of a unique susceptibility of neonates to infection with another Candida species, C. parapsilosis, to better define the response of neutrophils to a fungal pathogen. Neutrophils are known to be key effector cells in anti-fungal host defense, and have recently been shown to have a robust transcriptional response to infectious agents. We will use microarray technology to characterize the differences in response to this fungus between premature neutrophils and those from adults, in order to better understand the deficiencies that lead to susceptibility. Relevance: People who have weakened immune systems are increasing in number, leading to increases in serious infections. Understanding the specific mechanisms in the microbe and in the immune system that lead to these infections will enable the design of strategies to improve the immune system and better protect these patients from life-threatening disease.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 导致宿主免疫受损的情况改变了宿主和病原体之间的平衡，使某些人群特别容易感染传染病，死亡率和发病率加快。新生儿就是这样的宿主之一。保护性的宫内环境使得强大的免疫防御变得不必要。 然而，出生时发生的巨大生理和环境变化需要胎儿的每个系统进行适应，包括免疫系统。尽管即使是足月婴儿也需要几个月的时间才能完全发展出大龄儿童强大的宿主防御能力，但早产儿还面临着额外的挑战。由于体液免疫和细胞免疫受损，这些婴儿很容易受到感染。重要的是，一些成年人也存在类似的脆弱性。免疫损害发生在血液和实体器官恶性肿瘤、艾滋病毒/艾滋病和烧伤患者等多种情况下。因此，我们相信，鉴定早产儿中导致其感染易感性的宿主因素也将为其他免疫受损人群的脆弱机制提供信息。我们已经生成并表征了白色念珠菌菌丝（一种与毒力相关的生长形态）特异的单克隆抗体片段。具体目标1将通过cDNA文库筛选进一步确定这些抗体片段所识别的菌丝抗原。 我们还将通过构建这些基因的突变体并在鼠念珠菌病新生儿模型中检查它们的表型来检查这些抗原在生物体毒力中的作用。具体目标 2 将在真正的人 IgG 背景下表达这些抗体片段，并测试这些单克隆抗体在新生儿念珠菌病模型中预防播散性疾病的能力。具体目标 3 将利用新生儿对另一种念珠菌属（近平滑念珠菌）感染的独特敏感性，以更好地确定中性粒细胞对真菌病原体的反应。已知中性粒细胞是抗真菌宿主防御中的关键效应细胞，并且最近被证明对传染原具有强大的转录反应。我们将使用微阵列技术来表征早产中性粒细胞和成人中性粒细胞对这种真菌的反应差异，以便更好地了解导致易感性的缺陷。 相关性：免疫系统减弱的人数正在增加，导致严重感染的增加。了解导致这些感染的微生物和免疫系统的具体机制将有助于设计改善免疫系统的策略，并更好地保护这些患者免受危及生命的疾病的侵害。