Immune cell mechanisms of Bacillus anthracis sepsis

摘要 细菌性败血症是一种严重且难以治疗的疾病，死亡率很高，部分原因是最初的过度活跃。 先天免疫后免疫抑制，使宿主容易受到新的感染。吸入性 炭疽病，与生物恐怖主义有关的炭疽芽胞释放的已知和预期结果， 如不及早干预，将不可避免地导致败血症和高死亡率。抗炎脓毒症治疗 在老鼠身上进行的研究在人类身上失败了，这表明对人类免疫缺陷的分子机制的更好的理解 巴氏败血症需要人类免疫细胞的参与。我们中心之前的工作表明，未经检查的 死亡细胞释放的循环核小体升高会加重炎症和脓毒症的病理。 巨噬细胞通过胞泡吞噬过程来清除凋亡细胞。一个主要的网站 脓毒症时淋巴细胞的凋亡位于次级淋巴器官。小鼠组织巨噬细胞功能的研究 这些淋巴器官可能对脓毒症时淋巴细胞的凋亡性清除至关重要。我们的初步数据 表明BA及其毒素损害人单核细胞来源的巨噬细胞的泡腾功能，尽管其机制 目前还不清楚。在目标1中，我们将检验BA及其毒素抑制人类组织巨噬细胞的假设 泡腾通过减少泡腾机械的表达和破坏泡腾受体信号而起作用。 广泛的淋巴细胞凋亡也是免疫抑制的原因之一，免疫抑制是脓毒症后的主要并发症。 生死存亡。长期免疫抑制与低反应性T细胞蓄积有关 精疲力竭的标志，暗示参与了表观遗传变化。我们的初步数据显示 巴诱导的脓毒症灵长类动物模型中淋巴细胞减少和携带耗竭标志物的T细胞。在目标2中，我们将 验证活体BA及其毒素促进T淋巴细胞凋亡和衰竭的假设，导致 败血症后表观遗传学改变强化的免疫抑制T细胞表型。脂激活核 过氧化物酶体增殖物激活受体(PPAR)和肝X受体(LXRs)等受体对 脂类通过增加胞吐机械的转录而吞噬凋亡细胞。然而，很少有研究 评估了PPAR或LXR活性对人类组织巨噬细胞基因表达或淋巴细胞的影响 细胞凋亡。这些受体的合成激动剂已显示出对糖尿病和复发性中风的疗效，但没有 据我们所知，研究已经使用这种调节剂来治疗人类或灵长类动物的败血症。在《目标3》中，我们将 验证合成的PPAR和LXR激动剂可以缓解脂质激活核受体的假说 脓毒症时巴及其毒素对巨噬细胞和T细胞的负面影响。这些研究的结果 将有助于更好地理解急性病理和随后的免疫抑制的机制。 并可能加速开发治疗脓毒症患者的新治疗策略。

Summary Bacterial sepsis is a serious and difficult-to-treat condition with high mortality in part due to initial overactive innate immunity followed by immunosuppression that leaves the host vulnerable to new infections. Inhalational anthrax, a known and expected outcome of bioterrorism-related release of Bacillus anthracis (Ba) spores, inevitably leads to sepsis and high mortality without early intervention. Anti-inflammatory sepsis therapies developed in mice have failed in humans, indicating that improved understanding of molecular mechanisms of human immune cell involvement in Ba sepsis is needed. Prior work in our center showed that unchecked inflammation and sepsis pathology is worsened by elevated circulating nucleosomes released from dying cells. Clearance of apoptotic cells is mediated by macrophages via the process of efferocytosis. A major site of lymphocyte apoptosis in sepsis is in secondary lymphoid organs. Efferocytic function by tissue macrophages in these lymphoid organs is likely crucial for apoptotic lymphocyte clearance during sepsis. Our preliminary data show that Ba and its toxins impair human monocyte-derived macrophage efferocytosis, although the mechanism is unclear. In Aim 1, we will test the hypothesis that Ba and its toxins inhibit human tissue macrophage efferocytosis by decreasing expression of efferocytic machinery and impairing efferocytic receptor signaling. Extensive lymphocyte apoptosis also contributes to immunosuppression, a major complication following sepsis survival. Long term immunosuppression correlates with the accumulation of hyporesponsive T cells bearing markers of exhaustion, suggesting the involvement of epigenetic changes. Our preliminary data show lymphopenia and T cells bearing exhaustion markers in a primate model of Ba induced sepsis. In Aim 2, we will test the hypothesis that live Ba and its toxins promote T lymphocyte apoptosis and exhaustion, leading to immunosuppressed T cell phenotypes enforced by epigenetic changes after sepsis. Lipid-activated nuclear receptors such as peroxisome proliferator activated receptors (PPARs) and liver X receptors (LXRs) respond to lipids of efferocytosed apoptotic cells by increasing transcription of efferocytic machinery. However, few studies have assessed the impact of PPAR or LXR activity on human tissue macrophage gene expression or lymphocyte apoptosis. Synthetic agonists of these receptors have shown efficacy in diabetes and recurrent stroke but no studies to our knowledge have used such modulators to treat sepsis in humans or primates. In Aim 3, we will test the hypothesis that synthetic agonists of PPAR and LXR lipid-activated nuclear receptors can mitigate negative impacts of Ba and its toxins on macrophages and T cells during sepsis. The results of these studies will lead to a better understanding of mechanisms of acute pathology and subsequent immunosuppression in sepsis and may accelerate the development of new therapeutic strategies for the treatment of septic patients.