NEONATAL CANDIDIASIS & IMMUNE COMPROMISE DURING DEVELOPMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 导致宿主免疫妥协的条件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强大的免疫防御变得不必要。然而，出生时发生的戏剧性的生理和环境变化需要每个胎儿系统的适应，包括免疫。尽管即使是足月婴儿也需要几个月的时间才能完全形成大孩子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，这些婴儿容易受到感染。重要的是，在一些成年人群中也发现了类似的脆弱性。免疫妥协发生在各种情况下，如血液和实体器官恶性肿瘤、艾滋病毒/艾滋病和烧伤患者。因此，我们相信，确定早产儿感染易感性的宿主因素也将揭示其他免疫受损人群的易感性机制。我们已经产生并鉴定了针对白念珠菌菌丝的单抗片段，这是一种与毒力相关的生长形态。特异靶1将通过筛选cDNA文库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，并在小鼠新生儿念珠菌病模型中检查它们的表型，来检验这些抗原在生物体毒力中的作用。特异性目标2将在真实的人免疫球蛋白的背景下表达这些抗体片段，并在新生儿念珠菌病模型中测试这些单抗对播散性疾病的保护能力。具体目标3将利用新生儿对另一种念珠菌感染的独特敏感性，更好地确定中性粒细胞对真菌病原体的反应。中性粒细胞是已知的抗真菌宿主防御的关键效应细胞，最近被证明对感染性物质有很强的转录反应。我们将使用微阵列技术来表征早产儿中性粒细胞和成人中性粒细胞对这种真菌的反应差异，以更好地了解导致易感性的缺陷。相关性：削弱免疫系统的人数正在增加，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中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威胁生命的疾病的侵袭。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.