Myeloid Cell KLF2 and IL-4 in Histoplasmosis

描述（由申请人提供）：二态真菌，荚膜组织浆体（Hc），是美国中西部和东南部的地方性疾病，是真菌呼吸道感染的最常见原因。它在巨噬细胞的细胞内环境中茁壮成长。我们拟在体内研究转录因子KLF - 2如何调节髓细胞调节宿主对Hc反应的能力。KLF2在胚胎发生中是必不可少的，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细胞迁移有深远的影响。几乎没有关于它在炎症的个体发生和宿主对病原体的抗性中的重要性的信息存在。我们创造了一只骨髓细胞中缺乏KLF2的小鼠。初步数据表明，这些动物的Hc感染与白细胞介素(IL)-4的增加和更高的真菌负荷有关。缺乏kfl2的巨噬细胞表现出一种与Hc杀伤受损相关的替代激活表型。我们在此试图确定髓细胞中KLF2的缺失如何扭曲免疫反应。在目的1中，我们将确定KLF2切除是否会改变炎症反应和感染过程，我们将检查IL-4生成的年表。在目标2中，我们将确定IL-4的来源，并确定IL-25、-33或胸腺基质淋巴生成素（IL-4的三种诱导因子）是否在KLF2条件敲除中上调，如果上调，哪个细胞是来源。这一探索性建议将努力确定KLF2在宿主-微生物战斗中的必要性。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。

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.