Alarmin-mediated control of CNS infection

项目总结 感染会对大脑造成不可逆转的损害。在这项提案中，我们的目标是了解免疫系统如何 系统被动员到大脑的特定区域以消除病原体。弓形虫寄生虫 导致慢性脑部感染，寄生虫以细胞内包囊的形式持续存在。当包囊重新激活时， 强烈的免疫反应发生在这些限制寄生虫复制的区域。我们的初步数据和 最近的出版物强调了向大脑招募炎性单核细胞以控制感染的必要性。 将单核细胞来源的巨噬细胞募集到大脑，特别是募集到区域的炎性网络 关于包囊重新激活的问题尚未确定，这是这项提案的重点。在初步研究中，我们发现 两种宿主警报(从受损和死亡的细胞中释放的分子)是必需的，IL-33和IL-1α 将髓系细胞带入大脑，控制寄生虫负担。在这项提案中，我们将针对中央 假设IL-33和IL-1α通过非冗余的炎症途径作用于 单核细胞进入大脑以控制寄生虫的复制。具体来说，在目标1中，我们将研究关键的IL-33R- 在中枢神经系统中表达的细胞，我们假设它产生了趋化因子CCL2，驱动单核细胞 趋化性。在目标2中，我们建议研究在感染过程中释放和响应IL-1α的关键细胞。 我们假设IL-1α作用于内皮细胞诱导黏附分子表达 单核细胞进入大脑。在目标3中，我们将研究无法感知两个警报信号如何影响 控制感染。总体而言，这些研究将定义组织损伤如何驱动保护性免疫反应 大脑。由警报触发的炎症通路在多发性硬化的背景下引起极大的兴趣 神经炎性疾病，包括阿尔茨海默病，其中受体中的SNPs需要IL-2和 1α和IL-33信号转导、IL-1RAP与疾病进展有关。这些研究的结果可能 导致促进或防止大脑局部免疫反应的治疗方法的发展。

PROJECT SUMMARY Infections can cause irreversible damage to the brain. In this proposal, we aim to understand how the immune system is mobilized to specific regions of the brain to eliminate pathogens. The parasite Toxoplasma gondii causes a chronic brain infection where the parasite persists in an intracellular cyst form. When cysts reactivate, vigorous immune responses occur in these regions that limit parasite replication. Our preliminary data and a recent publication highlight the necessity of recruiting inflammatory monocytes to the brain to control infection. The inflammatory networks that recruit monocyte-derived macrophages to the brain and specifically to regions of cyst reactivate have not been identified and are the focus of this proposal. In preliminary studies, we find that two host alarmins (molecules that are released from damaged and dying cells), IL-33 and IL-1α, are necessary to bring myeloid cells into the brain and control parasite burden. In this proposal, we will address the central hypothesis that IL-33 and IL-1α act through non-redundant inflammatory pathways to drive the recruitment of monocytes to the brain to control parasite replication. Specifically, in Aim 1 we will examine the key IL-33R- expressing cells in the CNS, which we hypothesize make the chemokine, CCL2, that drives monocyte chemotaxis. In Aim 2, we propose to investigate the key cells that release and respond to IL-1α during infection. We hypothesize that IL-1α acts on the endothelium to induce adhesion molecule expression necessary for monocyte trafficking into the brain. In Aim 3 we will examine how the inability to sense both alarmins affects the control of infection. Overall, these studies will define how tissue damage drives protective immune responses in the brain. The inflammatory pathways triggered by alarmins are of great interest in the context of multiple neuroinflammatory conditions, including Alzheimer’s disease, where SNPs in the receptor required for both IL- 1α and IL-33 signaling, IL-1RAP have been linked to disease progression. The results from these studies may lead to the development of therapeutics that promote or prevent focal immune responses in the brain.