Lung and bone marrow crosstalk during a respiratory infection

描述(申请人提供)：在呼吸道感染时，免疫反应由促炎症细胞因子的爆发启动，随后大量细胞渗透到肺部。有证据表明，在感染早期进入肺的细胞将抗原运送到淋巴结，这有助于启动获得性免疫。我们的初步数据显示，在呼吸道病毒感染期间，与肺前炎症爆发相一致，血液中一些细胞因子的水平上升，随后骨髓细胞(BM)中的细胞发生显著变化。耐人寻味的是，BM中的细胞显示出一种“干扰素签名”，它涉及到许多抗病毒基因的表达。骨髓细胞的这些适应发生在骨髓中没有病毒感染或血液中没有检测到病毒的情况下。表达这种干扰素特征的骨髓细胞能抵抗多种病毒的感染。骨髓是主要的造血部位，很可能是炎症组织的促炎细胞的供应者。然而，有限的研究集中在局部肺部感染期间肺和骨髓之间的串扰。从骨髓中招募的单核细胞、粒细胞和其他非抗原特异性细胞对肺免疫的贡献也缺乏信息。我们假设，在病毒感染期间在肺中产生的信号被传递到骨髓，以诱导细胞的协同启动和释放到血液中，以补充到炎症的肺。当遇到肺部的病原体提示时，这些启动的细胞会有效地发挥作用。这笔赠款的目的1将研究在仙台病毒感染的小鼠模型中肺源性干扰素对骨髓细胞的影响，以及这种影响在免疫发展中的后果。BM中细胞暴露于干扰素可能与免疫的有效发展密切相关，因为I型干扰素预先处理树突状细胞，使其在体外对病毒感染产生高反应性。骨髓细胞是否被干扰素激活以抵抗病毒感染，同时准备好一旦被招募到肺部就能有效地对病毒信号做出反应？骨髓细胞的干扰素信号如何影响体内肺免疫的结果？目的2研究G-CSF和IL-6在肺部感染时骨髓细胞活化和释放中的作用。这些在经历肺部感染的动物的血液中高度升高的蛋白质与细胞分化和从骨髓中释放有关。总体而言，在这些研究中，我们希望确定肺部产生的细胞因子与肺病毒感染期间骨髓反应之间的特定相互作用。鉴于骨髓与造血的相关性，以及新招募的细胞在肺免疫发展中的作用，阐明这两个隔室之间的串扰机制可能为治疗和疫苗接种过程中粘膜免疫的调节创造新的干预模式。在呼吸道病毒感染期间，肺源性信号和骨髓细胞之间的相互作用被忽视了。我们已经确定了在对局限于肺部的病毒感染的免疫反应开始期间，骨髓细胞的一些变化。在这项资助中，我们的目的是描述肺源性细胞因子和骨髓细胞的相互作用以及这种相互作用对粘膜免疫发展的影响。我们希望在肺和骨髓的串扰过程中确定调节通路，这些通路可以作为操纵粘膜免疫的新的干预点。

DESCRIPTION (provided by applicant): Upon respiratory infection, the immune response is initiated by a burst of pro-inflammatory cytokines, followed by a massive infiltration of cells to the lung. Evidence suggests that cells infiltrating the lung early during infection transport antigen to the lymph nodes which contributes to the initiation of adaptive immunity. Our preliminary data demonstrated that during a respiratory viral infection, in concordance with the lung pro-inflammatory burst, the levels of a number of cytokines rise in the blood followed by significant changes in cells in the bone marrow (BM). Intriguingly, the cells in the BM display an "interferon signature" which involves the expression of a number of anti-viral genes. These adaptations of BM cells occur in the absence of virus infection in the BM or detectable virus in the blood. BM cells expressing this interferon signature are resistant to infection by a number of viruses. The BM, the primary site of hematopoiesis, is a likely supplier of pro-inflammatory cells to inflamed tissues. However, limited research has been done focusing on the crosstalk between the lung and the BM during a localized lung infection. Information regarding the contribution of monocytes, granulocytes, and other non-antigen specific cells recruited from the BM for lung immunity is also lacking. We hypothesize that signals produced in the lung during a viral infection are delivered to the BM to induce the concerted priming and release of cells to the blood for recruitment to the inflamed lung. These primed cells perform effectively when encountering pathogen cues in the lung. Aim 1 of this grant will study the effect of lung derived interferons in BM cells during a well characterized model of mice infection with Sendai virus, and the consequences of this effect in the development of immunity. The exposure of cells to interferons in the BM could be greatly relevant for the effective development of immunity as pre-treatment of dendritic cells with type I IFN renders them hyperresponsive to virus infection in vitro. Are BM cells primed by interferon to resist virus infection while prepared to effectively respond to viral cues once recruited to the lung? How does the interferon signature of BM cells affect the outcome of lung immunity in vivo? Aim 2 will study the role of G-CSF and IL-6 in the activation and release of cells from the BM during lung infection. These proteins that are highly elevated in the blood of animals undergoing a lung infection have been associated with cell differentiation and release from the BM. Overall, in these studies we expect to define specific interactions between cytokines produced in the lung and the BM response during a lung viral infection. Given the relevance of the BM for hematopoiesis, and the demonstrated role of newly recruited cells for the development of lung immunity, the elucidation of the mechanism of crosstalk between these two compartments could create novel modes of intervention for the modulation of mucosal immunity during therapy and vaccination. The interaction between lung-derived signals and bone marrow cells during a respiratory virus infection has been overlooked. We have identified a number of changes in bone marrow cells during the onset of the immune response to a viral infection restricted to the lung. In this grant we aim to characterize the interaction of lung-derived cytokines and bone marrow cells and the effect of this interaction for the development of mucosal immunity. We expect to identify regulatory pathways during the crosstalk of lung and bone marrow that could serve as novel points of intervention for the manipulation of mucosal immunity.