The Genetic Determinants of Innate Immunity and Host Defense

该项目的目标是识别与先天免疫有关的新基因，并确定其中一些基因的多态性是否调节人类对内毒素(LPS)、金黄色葡萄球菌、革兰氏阴性败血症和烟曲霉感染的先天免疫反应。 我们之前已经证明，在小鼠和人类中，内毒素受体TLR4的多态与对吸入内毒素的低反应有关。我们还表明，这些相同的基因多态性使人类容易患上革兰氏阴性脓毒症，并保护他们免受动脉粥样硬化的影响。然而，我们以前的发现也表明，TLR4的序列变体只占小鼠或人类的部分内毒素表型，其他基因也参与调节对内毒素的反应。 宿主易感性在革兰氏阴性菌和革兰氏阳性菌引起的感染的起始和严重程度中的作用尚不完全清楚。我们败血症项目的总体目标是进一步了解为什么有些人会发生感染，而那些患有菌血症的人，为什么只有一些人会有不良后果。同样，对宿主对烟曲霉的先天免疫反应知之甚少。烟曲霉是一种真菌病原体，会在免疫受损的宿主中导致侵袭性肺曲霉病。 这个研究项目的总体假设是，在用微生物毒素或模型系统(小鼠、线虫和细胞培养)中的活生物体挑战后，通过遗传或基因组技术确定的基因的多态调节人类对先天性免疫刺激的病理生理反应。为了验证这一假设，将在小鼠身上进行基因表达和位置克隆研究，并将在人类身上测试它们的遗传相关性。我们还将在哺乳动物组织培养和线虫中使用RNA干扰(RNAi)来测试这些基因的生理和生物学重要性。

The goals of this project are to identify novel genes involved in innate immunity and to determine if polymorphisms in some of these genes regulate the innate immune response to lipopolysaccharide (LPS), Staphylococcus aureus, Gram negative sepsis, and Aspergillus fumigatus infection in humans. We have previously shown that polymorphisms in TLR4, the receptor for LPS, are associated with hyporesponsiveness to inhaled LPS in mice and humans. We have also shown that these same polymorphisms predispose humans to Gram negative sepsis and protect them from atherosclerosis. However, our previous findings also demonstrate that sequence variants of TLR4 account for only a portion of the LPS phenotype in either mice or humans and that other genes are also involved in regulating the response to LPS. The role of host susceptibility in the initiation and severity of infections caused by Gram negative and Gram positive bacteria is incompletely understood. The overall goal of our sepsis project is to further understand why some individuals develop infection, and of those with bacteremia, why only some go on to have adverse outcomes. Similarly, very little is known about the hosts innate immune response to Aspergillus fumigatus, a fungal pathogen that causes invasive pulmonary aspergillosis in immunocompromized hosts. The overall hypothesis of this research program is that polymorphisms of genes identified either by genetic or genomic techniques following a challenge with a microbial toxin or a live organism in model systems (mice, C. elegans, and cell culture) regulate the pathophysiologic response to innate immune stimuli in humans. To test this hypothesis, gene expression and positional cloning studies will be conducted in mice and their genetic relevance will be tested in humans. We will also use RNA interference (RNAi) in mammalian tissue culture and the nematode C. elegans to test the physiologic and biologic importance of these genes.