Macrophage differentiation and disease outcome in influenza infection

项目概要/摘要 单核细胞和巨噬细胞（Mφ）感知病原体的存在、组织损伤和宿主来源的免疫应答。 介质在他们的环境和响应分化成不同的功能表型，介导 宿主先天免疫反应。Mφ的分化过程常被描述为“可塑性的”， 这意味着这些细胞通过快速可逆的分化步骤来调节它们的功能， 对宿主的环境变化做出反应。例如，“经典激活”的Mφ（CAM; M1）是高度激活的。 它们具有杀微生物作用，但它们产生的炎性细胞因子和一氧化氮也可能损害宿主组织。在 功能谱的另一端，由IL-4和IL-13诱导的“交替活化”Mφ（AAM或M2）， 通过消除受损组织和其他抗炎机制介导“伤口愈合”。Dur- 在过去的三十年里，PI进行了旨在解剖复杂分子的研究， Mφ分化的抑制以及这如何影响宿主防御和疾病结果。在拟议的研究中- 即，要检验的中心假设是，激活特定的细胞内信号通路远端的en， 流感诱导的PAMP和DAMP对TLR 4和/或其他信号受体的激动作用有助于促进 革兰氏阳性表达的促炎和抗炎基因的离散盒，控制的方式， 宿主Mφ对感染有反应。提出了两个具体的目的，以在体外和体内检验这一假设， 最终目标是确定新的治疗干预措施，用于需要Mφ来控制的疾病， 消灭入侵的病原体和/或解决由病原体或宿主炎症反应引起的组织损伤， 感染时会有反应。雄性和雌性小鼠（由于基因工程菌株的可用性）， 和棉鼠（对人类非适应性流感分离株特别敏感）将被用作 原发性（10）流感感染和10流感感染随后继发性（20）细菌感染的模型， 是的。所提出的创新性实验方法旨在：（1）识别TLR 4相互作用的信号传导 受体（即，PAR 2，CD 11b/CD 18），并描述这些相互作用对调节的贡献 Mφ分化/对流感感染的易感性;和（2）鉴定流感触发的、表观遗传的和/或 介导对2 o革兰氏阳性细菌感染的易感性的Mφ分化机制。在会议结束时， 这些综合性研究的锡永，决定TLR激动剂相互作用的关键过程， Mφ激活的变化将被定义，反过来，可以预期转化为合理的， 用于控制入侵的病原体或对抗炎症损伤的实用治疗方法， 病原体诱导的组织，最终提供循证疗法来治疗感染性疾病。

PROJECT SUMMARY/ABSTRACT Monocytes and macrophages (Mφ) sense the presence of pathogens, tissue damage, and host-derived mediators in their environment and respond by differentiating into distinct functional phenotypes that mediate host innate immune responses. The process of Mφ differentiation has often been described in terms of “plastic- ity,” implying that these cells modulate their functions through rapidly reversible differentiation steps in re- sponse to environmental changes in the host. For example, “classically activated” Mφ (CAM; M1) are highly microbicidal, yet their production of inflammatory cytokines and nitric oxide may also damage host tissue. At the other end of the functional spectrum, “alternatively activated” Mφ (AAM or M2), induced by IL-4 and IL-13, mediate “wound healing” through elimination of damaged tissue and other anti-inflammatory mechanisms. Dur- ing the past three decades, the PI has undertaken research designed to dissect the complex molecular under- pinnings of Mφ differentiation and how this impacts host defenses and disease outcome. In the proposed stud- ies, the central hypothesis to be tested is that activation of specific intracellular signaling pathways distal to en- gagement of TLR4 and/or other signaling receptors by influenza-induced PAMPs and DAMPs serve to pro- gram expression of discrete cassettes of pro- and anti-inflammatory genes that control the manner in which the host Mφ responds to infection. Two Specific Aims are proposed to test this hypothesis in vitro and in vivo, with the ultimate goal of identifying novel therapeutic interventions for diseases where Mφ are required for contain- ing the invading pathogen and/or resolving tissue damage caused by pathogens or the host inflammatory re- sponse to infection. Both male and female mice (because of the availability of genetically engineered strains), and cotton rats (that are uniquely susceptible to human non-adapted isolates of influenza) will be utilized as models of primary (1o) influenza infection and 1o influenza infection followed by secondary (2o) bacterial infec- tion. The proposed innovative experimental approaches are designed to: (1) identify TLR4-interacting signaling receptors (i.e., PAR2, RAGE, CD11b/CD18) and delineate the contributions of these interactions to regulation of Mφ differentiation/susceptibility to influenza infection; and, (2) identify influenza-triggered, epigenetic and/or Mφ differentiative mechanisms that mediate susceptibility to 2o Gram-positive bacterial infection. At the conclu- sion of these comprehensive studies, key processes that govern interactions of TLR agonists that lead to changes in Mφ activation will have been defined that, in turn, can be expected to translate into reasonable and practical therapeutic approaches for controlling invading pathogens or counteracting inflammatory damage to tissues induced by pathogens, ultimately providing evidence-based therapies to treat infectious diseases.