Role of CCR1 in Cytokine Storm & Immunopathology after influenza infection

感染高致病性流感病毒(包括禽流感H5N1病毒和1918年H1N1病毒)后的死亡率与这些病毒诱导严重的细胞因子介导的免疫病理的倾向有关，以低氧血症和出血性炎症性肺水肿为特征。此外，在感染甲型流感病毒的儿童中，急性促炎细胞因子的产生与致命的流感相关脑病的发病有关。抗病毒神经氨酸酶抑制剂能够 如果患者及早给药，可以控制病毒感染，但目前还没有治疗细胞因子介导的肺损伤的药物报道。重要的是，流感感染过程中致病细胞因子的确切来源尚未确定。然而，在几种炎症性肺部疾病中，单核细胞来源的细胞在肺内的积累与肺损伤的发展有关，这些细胞已经 提示流感感染后炎性细胞因子的主要来源。流感感染后，炎性髓系细胞向肺部招募、分化和激活的机制仍然难以捉摸。趋化因子受体CCR1由造血细胞表达，包括单核细胞、巨噬细胞和树突状细胞，以及一些非骨髓源性细胞。我们的初步数据表明，CCR1缺失可以预防与致死性流感感染相关的免疫病理学和死亡率。基于 根据我们的初步结果，我们假设CCR1缺乏通过阻止感染肺内单核细胞来源的炎症细胞的激活来防止流感相关死亡。在这项提案中，我们将确定CCR1缺乏如何促进对与致病性流感感染相关的免疫病理学的保护(目标1)，并将评估CCR1拮抗剂在治疗流感相关免疫病理学方面的潜在治疗用途(目标2)。

Mortality after infection with highly pathogenic influenza viruses, including avian H5N1 virus and the 1918 H1N1 virus, is associated with the propensity of these viruses to induce severe cytokine-mediated immunepathology, characterized by hypoxemia and hemorrhagic inflammatory edema in the lung. In addition, acute pro-inflammatory cytokine production has been correlated with the onset of fatal influenza-associated encephalopathy in children infected with influenza A viruses. Antiviral neuraminidase inhibitors are able to control viral infection if given early to patients, but no drugs have been reported to be effective in treating the cytokine-mediated lung damage. Importantly, the exact source of pathogenic cytokines during influenza infection has been not identified. However, accumulation of monocyte-derived cells in the lungs is associated with the development of lung damage in several inflammatory pulmonary diseases, and these cells have been suggested the major source of inflammatory cytokines after influenza infection. Mechanisms orchestrating the recruitment, differentiation and activation of inflammatory myeloid cells to the lung following flu infection remain elusive. The chemokine receptor CCR1 is expressed by hematopoietic cells, including monocytes, macrophages and DCs, and by some non-bone marrow-derived cells. Our preliminary data demonstrate that CCR1 deletion protects from lethal influenza infection associated immunopathology and mortality. Based on our preliminary results, we hypothesize that CCR1 deficiency prevents influenza-associated mortality by preventing activation of monocyte-derived inflammatory cells within the infected lungs. In this proposal, we will determine how CCR1 deficiency promotes protection from the immunopathology associated with pathogenic influenza infections (Aim 1) and will evaluate the potential therapeutic uses of CCR1 antagonists in treating influenza-associated immunopathology (Aim 2).