B. anthracis Peptidoglycan as a Pro-inflammatory Agent in Anthrax Pathogenesis

关于吸入性炭疽病的大部分工作都专门集中在外毒素上。我们最近的研究 表明炭疽杆菌细胞壁的肽聚糖成分诱导产生 炎性细胞因子和趋化因子。细胞因子和趋化因子的产生是唯一的 外周血单核细胞；淋巴细胞和中性粒细胞无反应。我们有初步的和 正在进行的结构工作，以确定炭疽杆菌肽聚糖的化学特征。我们有新的工具来 鉴定目前未知的革兰氏阳性肽聚糖的胞外受体，并了解 由受体诱导的信号事件，并引起单核细胞生物学的变化。此外，我们 有新的数据表明，肽聚糖诱导单核细胞凋亡的亚群不同于 单核细胞产生炎性细胞因子。我们提出了一个实验计划来确定这一机制。 由肽聚糖引发的细胞凋亡。单核细胞凋亡可能是B细胞高死亡率的原因之一。 炭疽杆菌和可能的其他革兰氏阳性病原体通过消除 先天免疫系统。我们将通过挑战啮齿动物和非人类灵长类动物来测试这种可能性。 炭疽菌肽聚糖和测量单核细胞水平。

Much of the work on inhalation anthrax has exclusively focused on the exotoxins. Our recent studies ndicate that the peptidoglycan component of the B. anthracis cell wall induces the production of nflammatory cytokines and chemokines. The production of the cytokines and chemokines is exclusively from peripheral blood monocytes; lymphocytes and neutrophils do not respond. We have preliminary and on-going structural work to chemically characterize B. anthracis peptidoglycan. We have novel tools to identify the currently unknown extracellular receptor for Gram-positive peptidoglycan and to understand the signaling events induced by the receptor and causing the changes in monocyte biology. Additionally, we have new data indicating that peptidoglycan induces monocyte apoptosis in a subpopulation distinct from the monocytes producing inflammatory cytokines. We present an experimental plan to identify the mechanism of peptidoglycan-triggered apoptosis. The monocyte apoptosis might contribute to the high mortality of B. anthracis and possibly of other Gram-positive pathogens by eliminating an important component of the innate immune system. We will test this possibility by challenging rodents and non-human primates with B. anthracis peptidoglycan and measuring monocyte levels.