Host Defense Against Infection and Dietary Fatty Acids

描述（由申请人提供）：已知膳食脂肪酸可调节免疫防御系统。然而，这种调制的基本机制还没有很好地理解。我们以前的研究结果表明，饱和脂肪酸激活Toll样受体（TLR），导致NF κ B激活和有丝分裂原诱导型环氧合酶（考克斯-2）在巨噬细胞中的表达。然而，测试的所有不饱和脂肪酸抑制由饱和脂肪酸或细菌脂多糖（LPS）诱导的TLR活化。N-3多不饱和脂肪酸（PUFAs）与n-6 PUFAs相比，优先抑制巨噬细胞TLR介导的信号通路的激活和靶基因的表达。这些结果证明了脂肪酸调节受体介导的信号通路和靶基因表达的新机制，并表明TLR介导的靶基因表达和免疫反应可以通过膳食脂肪酸的类型来调节。下一个问题是这种调制的功能后果是什么。TLR在识别入侵的微生物病原体和诱导先天性和适应性免疫应答以消除感染性微生物中起主要作用。作为我们以前研究的逻辑延伸，我们建议在这里确定饮食脂肪酸组成的变化是否可以改变免疫反应和随后的宿主对感染的防御，并阐明脂肪酸调节感染诱导的先天性和适应性免疫反应的机制。具体目标是：1）确定饱和脂肪酸激活TLR 4和TLR 2二聚体而多不饱和脂肪酸抑制激活的机制。2)鉴定受饱和脂肪酸和多不饱和脂肪酸差异调节的靶基因; 3）使用动物模型确定饱和脂肪酸和不饱和脂肪酸是否由于调节TLR信号通路和靶基因表达而改变免疫应答; 4）确定饮食脂肪酸的类型是否改变动物模型中宿主对细菌感染的易感性。从拟议的研究结果将提供一个全面的图片TLR衍生的信号通路和靶基因表达的调制不同类型的脂肪酸如何导致不同的免疫反应和宿主防御入侵的微生物病原体。此外，从这些研究中获得的机制信息将使我们更好地了解感染如何增加患某些慢性疾病的风险，以及如何通过饮食方式降低这些风险。

DESCRIPTION (provided by applicant): Dietary fatty acids are known to modulate immunological defense systems. However, underlying mechanisms for such modulation are not well understood. Results from our previous studies demonstrated that saturated fatty acids activate Toll-like receptors (TLRs) leading to NFkappaB activation and the expression of mitogen inducible cyclooxygenase (COX-2) in macrophages. However, all unsaturated fatty acids tested inhibit TLR activation induced by saturated fatty acids or bacterial lipopolysaccharide (LPS). N-3 polyunsaturated fatty acids (PUFAs) as compared with n-6 PUFAs preferentially inhibit the activation of TLRmediated signaling pathways and target gene expression in macrophages. These results document novel mechanism by which fatty acids modulate receptor-mediated signaling pathways and target gene expression, and suggest that TLR-mediated target gene expression and immune responses can be modulated by types of dietary fatty acids. The next question is what the functional consequence of this modulation is. TLRs play a major role in recognition of invading microbial pathogens and induction of innate and adaptive immune responses for elimination of infecting microbes. As a logical extension of our previous studies, we propose here to determine whether changes in the dietary fatty acid composition can alter immune responses and subsequent host defense against infection, and to elucidate the mechanisms by which fatty acids modulate infection-induced innate and adaptive immune responses. The specific aims are: 1) To determine mechanisms by which saturated fatty acids activate TLR4 and TLR2 dimers, but polyunsaturated fatty acids inhibit the activation. 2) To identify target genes that are differentially regulated by saturated and polyunsaturated fatty acids; 3) To determine whether saturated and unsaturated fatty acids alter immune responses as a result of modulation of TLR-signaling pathways and target gene expression using animal models; 4) To determine whether types of dietary fatty acids alter susceptibility of the host to bacterial infection in animal models. Results from proposed studies will provide a comprehensive picture as to how the modulation of TLR-derived signaling pathways and target gene expression by different types of fatty acids leads to differential immune responses and host defense against the invading microbial pathogens. In addition, the mechanistic information gained from these studies will enhance our understanding as to how infections can increase risks of developing certain chronic diseases and how such risks can be reduced by dietary means.