Mechanisms of Impaired Neutrophil Responses in PostInfluenza Bacterial Pneumonia

流感后细菌性肺炎中中性粒细胞反应受损的机制

基本信息

批准号：
9272520
负责人：
Jane C Deng
金额：
$ 31.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-13 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272520
关键词：
Address Alveolar Macrophages Animals Anti-Bacterial Agents Antibiotics Antiviral Agents Applications Grants Bacterial Infections Bacterial Pneumonia Bone Marrow CXCL1 gene Cells Cessation of life Clinical Complication Data Defect Development Experimental Models Failure Family Genes Goals Grant Host Defense Human IL8RB gene Immune Immune response Immunosuppression Impairment In Vitro Individual Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Interferon Type I Interferons Interleukin-12 Interleukins Kinetics Leukocytes Ligands Lung Mediating Mediator of activation protein Morbidity - disease rate Mus Natural Immunity Neutrophil Infiltration Outcome Pathway interactions Phagocytosis Pneumonia Predisposition Production Protein Family Public Health Publishing Regulation Research Risk Role Secondary to Signal Transduction Source Streptococcal Infections Streptococcus pneumoniae Testing Virus Diseases bactericide base chemokine cytokine fighting gain of function in vivo insight loss of function member mortality neutrophil novel pandemic disease pandemic influenza response restoration secondary infection superinfection targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Influenza is an enormous public health threat worldwide, resulting in up to 500,000 deaths annually and manifold more during pandemics. Secondary bacterial pneumonias are a major fatal complication of influenza, through mechanisms which remain poorly elucidated. The long-term goal of my research is to unravel the mechanisms responsible for influenza-induced immunosuppression of antibacterial host defense in the lung, with the immediate objective of this proposal being to examine the role of type I interferons (IFNs) and IL-27 as critical mediators of neutrophil responses during post-influenza pulmonary infections by Streptococcal pneumoniae, which is the most significant cause of bacterial pneumonia worldwide. Our published data show that type I interferons (IFNs) induced during influenza infection suppress early neutrophil responses against secondary S. pneumoniae infection, resulting in impaired bacterial clearance and increased mortality. This is attributable to type I IFN-mediated suppression of CXCR2 ligands, KC (CXCL1) and MIP-2 (CXCL2), which are critical to neutrophil recruitment, and we furthermore show that early restoration of these chemokines reverses the defects in bacterial clearance following influenza. Our subsequent studies reveal that IL-27, a novel member of the IL-12 family of heterodimeric cytokines, is an IFN-regulated gene that is induced during influenza infection and acts as a negative regulator of KC and MIP2 production and neutrophil recruitment during post-influenza bacterial pneumonia. We therefore hypothesize that during influenza infection, type I IFNs mediate impairment of neutrophil responses against secondary S. pneumoniae infection by inducing the expression of IL-27. To test this hypothesis, we will perform studies with the following aims: 1. To determine the role of IL-27 in type I IFN-mediated susceptibility to post-influenza bacterial pneumonia; and 2. To determine the mechanisms by which IL-27 suppresses neutrophil responses. Using gain-of-function and loss of function approaches, the proposed studies will examine the in vivo role of IL-27 as a mechanism through which IFNs inhibit early neutrophil responses and impair bacterial clearance. Furthermore, we will examine the direct mechanisms through which IL-27 modulates neutrophil responses against post-influenza bacterial pneumonia using a combination of in vivo and in vitro approaches. The results of these studies will provide important mechanistic insights into how early neutrophil responses are impaired during post-influenza bacterial pneumonias, as well as further our understanding of the role of type I IFNs during bacterial infections. Furthermore, since little is known about the role f IL-27 in innate immunity and infection, the studies proposed are likely to advance the field by providing new information about how IL-27 regulates neutrophil responses, particularly in the context of a highly important clinical problem. Finally, given the ongoing global impact of influenza infections, the results of these studies will determine whether IL-27 is an IFN-regulated molecule that may be therapeutically manipulated to reverse influenza-induced impairment of pulmonary host defense.

描述（由申请人提供）：流感是全球范围内的一个巨大的公共卫生威胁，每年导致多达 50 万人死亡，在大流行期间导致更多人死亡。继发性细菌性肺炎是流感的一种主要致命并发症，其机制尚不清楚。我研究的长期目标是揭示流感诱导的肺部抗菌宿主防御免疫抑制的机制，该提案的直接目标是检查 I 型干扰素 (IFN) 和 IL-27 的作用作为流感后肺炎链球菌肺部感染期间中性粒细胞反应的关键介质，肺炎链球菌是全世界细菌性肺炎的最重要原因。我们发表的数据显示，流感感染期间诱导的 I 型干扰素 (IFN) 会抑制中性粒细胞对继发性肺炎链球菌感染的早期反应，导致细菌清除受损并增加死亡率。这归因于 I 型 IFN 介导的 CXCR2 配体、KC (CXCL1) 和 MIP-2 (CXCL2) 的抑制，这些配体对中性粒细胞募集至关重要，而且我们还表明，这些趋化因子的早期恢复可以逆转细菌清除的缺陷。流感。我们随后的研究表明，IL-27 是异二聚体细胞因子 IL-12 家族的新成员，是一种 IFN 调节基因，在流感感染期间诱导，并在感染后充当 KC 和 MIP2 产生以及中性粒细胞募集的负调节因子。 - 流感细菌性肺炎。因此，我们假设在流感感染期间，I 型干扰素通过诱导 IL-27 的表达来介导中性粒细胞针对继发性肺炎链球菌感染的反应受损。为了检验这一假设，我们将进行以下研究： 1. 确定 IL-27 在 I 型 IFN 介导的流感后细菌性肺炎易感性中的作用； 2.确定IL-27抑制中性粒细胞反应的机制。拟议的研究将使用功能获得和功能丧失的方法来检查 IL-27 作为 IFN 抑制早期中性粒细胞反应和损害细菌清除的机制的体内作用。此外，我们将结合体内和体外方法研究 IL-27 调节中性粒细胞针对流感后细菌性肺炎反应的直接机制。这些研究的结果将为了解流感后细菌性肺炎期间早期中性粒细胞反应如何受损提供重要的机制见解，并进一步了解 I 型干扰素在细菌感染期间的作用。此外，由于对 IL-27 在先天免疫和感染中的作用知之甚少，因此提出的研究可能通过提供有关 IL-27 如何调节中性粒细胞反应的新信息来推进该领域的发展，特别是在一个非常重要的临床背景下。问题。最后，考虑到流感感染对全球的持续影响，这些研究的结果将确定 IL-27 是否是一种 IFN 调节的药物。可以通过治疗手段逆转流感引起的肺部宿主防御损伤的分子。