Myeloid Cell KLF2 and IL-4 in Histoplasmosis

描述(申请人提供)：二相性真菌，组织胞浆菌(HC)，地方性在美国中西部和东南部，是最常见的真菌呼吸道感染的原因。它在巨噬细胞的细胞内环境中茁壮成长。我们建议研究转录因子Kr？ppel like factor2如何在体内调节髓系细胞调节宿主对HC的反应的能力。KLF2在胚胎发育中是必不可少的，在促炎细胞因子和趋化因子的产生中起着分子开关的作用，并对T细胞的迁移产生深远的影响。几乎没有关于它在炎症个体发生和宿主对病原体抵抗力中的重要性的信息。我们创造了一只在髓系细胞中缺乏KLF2的小鼠。初步数据表明，这些动物中的HC感染与白细胞介素4(IL-4)的增加和较高的真菌负担有关。缺乏KFL2的巨噬细胞表现出一种交替激活的表型，这与HC的杀伤受损有关。在此，我们试图确定KLF2在髓系细胞中的缺失如何影响免疫反应。在目标1中，我们将确定切除KLF2是否会改变炎症反应和感染过程，并将检查IL-4产生的年表。在目标2中，我们将确定IL-4的来源，并确定IL-4的三个诱导物IL-25、-33或胸腺间质淋巴生成素是否在KLF2条件基因敲除中上调，如果是，哪个细胞是来源。这一探索性的建议将努力确定KLF2在宿主-微生物之战中的必要性。我们的发现可能远远超出HC的范围，并适用于其他细胞内病原体和炎症性疾病。 公共卫生相关性：这项拨款旨在了解转录因子免疫组织胞浆菌病的作用。这种被称为Krppel样因子的基因调节免疫系统所必需的分子的产生。在这里，我们试图确定该基因如何调节一种加重组织胞浆菌病的细胞因子的产生。

DESCRIPTION (provided by applicant): The dimorphic fungus, Histoplasma capsulatum (Hc), is endemic to the midwestern and southeastern US and is the most frequent cause of fungal respiratory infection. It thrives within the intracellular environment of macrophages. We propose to investigate how the transcription factor, Kr¿ppel like factor (KLF) 2, modulates the ability of myeloid cells to regulate the host response to Hc in vivo. KLF2 is essential in embryogenesis, acts as a molecular switch in the generation of pro-inflammatory cytokines and chemokines, and exerts a profound effect on T cell migration. Virtually no information exists concerning its importance in the ontogeny of inflammation and host resistance to pathogens. We have created a mouse that lacks KLF2 in myeloid cells. Preliminary data indicate that Hc infection in these animals is associated with an increase in interleukin (IL)-4 and a higher fungal burden. KFL2-deficient macrophages manifest an alternatively activated phenotype that is associated with impaired killing of Hc. We seek herein to determine how the absence of KLF2 in myeloid cells skews the immune response. In aim 1, we will determine if KLF2 excision alters the inflammatory response and course of infection and we will examine the chronology of IL-4 generation. In aim 2, we will identify the origins of IL-4 and determine if IL-25, -33 or thymic stromal lymphopoietin, three inducers of IL-4, are upregulated in the KLF2 conditional knockouts and if so, which cell is the source. This exploratory proposal will endeavor to establish the necessity of KLF2 in the host-microbe battle. Our findings are likely to extend far beyond the scope of Hc and apply to other intracellular pathogens and to inflammatory diseases. PUBLIC HEALTH RELEVANCE: This grant seeks to understand the role of a transcription factor immunity to histoplasmosis. The gene known as Kr¿ppel like factor regulates production of molecules that are necessary for the immune system. Here, we seek to determine how this gene regulates the production of a cytokine that worsens histoplasmosis.