Dynamics of neutrophil trafficking in Granulocytic Anaplasmosis

描述（申请人提供）：嗜吞噬细胞无形体是一种蜱传专性细胞内细菌病原体，是人类和动物粒细胞无形体病的病原体。A.嗜吞噬细胞菌主要感染中性粒细胞（PMN），破坏正常的PMN凋亡和杀伤机制以促进细菌增殖。与内毒素阳性细菌感染相反，A.尽管骨髓（BM）粒细胞生成增加，但嗜吞噬细胞菌感染诱导中性粒细胞减少症。这意味着，这种嗜粒细胞的病原体可能从根本上改变上游调节的PMN动员，下游调节的PMN从BM释放和感染过程中的系统性运输和PMN归巢。 中性粒细胞减少和造血系统改变可能是导致A.嗜吞噬细胞菌感染，包括机会性感染，但在A.嗜吞噬细胞菌感染在很大程度上未知。我们的总体假设是A.嗜吞噬细胞菌感染和病原体复制扰乱正常的PMN运输，并可能最终促进病原体-PMN相互作用和增强细菌繁殖。将通过对中间信号传导和整合素介导的相互作用的影响，研究作为BM中PMN动员的上游调节因子的粒细胞集落刺激因子（G-CSF）和白细胞介素-8（IL-8）的诱导产生。将使用复杂的成像策略来定义系统性PMN运输和脾脏归巢。将确定中性粒细胞运输的机制，包括趋化梯度和整合素介导的相互作用在脾脏。我们的目标是确定感染诱导的中性粒细胞运输的机制，并确定其在先天免疫反应和疾病的临床后果中的作用。 K 01奖将支持Jennifer Johns博士作为博士后DVM，PhD的职业发展，并为她的独立研究做好准备。Johns博士是一位经验丰富的兽医临床病理学家，对传染病的血液学和造血系统改变特别感兴趣，并致力于先进的生物医学研究。要求提供五年的辅导支持。

DESCRIPTION (provided by applicant): Anaplasma phagocytophilum is a tick-borne obligate intracellular bacterial pathogen and the agent of granulocytic anaplasmosis in humans and animals. A. phagocytophilum primarily infects neutrophils (PMNs), subverting normal PMN apoptosis and killing mechanisms to facilitate bacterial proliferation. In contrast to endotoxin-positive bacterial infections, A. phagocytophilum infection induces neutropenia despite increased bone marrow (BM) granulopoiesis. The implication is that this granulocytotropic pathogen may fundamentally alter the upstream regulation of PMN mobilization, the downstream regulation of PMN release from BM and the systemic trafficking and homing of PMN during infection. Neutropenia and hematopoietic alterations likely contribute to the serious clinical complications of A. phagocytophilum infection, including opportunistic infections, but the mechanisms involved in altered PMN trafficking during A. phagocytophilum infection are largely unknown. Our global hypothesis is that A. phagocytophilum infection and pathogen replication perturb normal PMN trafficking and may ultimately facilitate pathogen-PMN interaction and enhance bacterial propagation. Infection-induced production of granulocyte colony stimulating factor (G-CSF) and interleukin-8 (IL-8) will be investigated as upstream regulators of PMN mobilization from BM via effects on intermediate signaling and integrin-mediated interactions. Systemic PMN trafficking and splenic homing will be defined using sophisticated imaging strategies. Mechanisms of PMN trafficking including chemotactic gradients and integrin-mediated interactions in the spleen will be determined. Our goal is to define mechanisms of infection-induced PMN trafficking and to determine their role in the innate immune response and clinical consequences of disease. The K01 award would support Dr. Jennifer Johns' career development as a postdoctoral DVM, PhD and prepare her for independent research. Dr. Johns is an experienced, board-certified veterinary clinical pathologist with a specific interest in hematologic and hematopoietic alterations in infectious disease and a commitment to advanced biomedical research. Five years of mentored support is requested.