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巨大公共卫生威胁，每年最多可死亡500,000人死亡，并在大流行期间更多。次要细菌性肺炎是流感的主要致命并发症，通过阐明的机制尚不确定。我的研究的长期目标是阐明肺部抗菌宿主防御的免疫抑制的机制全球细菌性肺炎的原因。我们发表的数据表明，在流感感染期间诱导的I型干扰素（IFN）抑制了针对继发性肺炎链球菌感染的早期嗜中性粒细胞反应，从而导致细菌清除率受损和死亡率增加。这归因于I型IFN介导的CXCR2配体抑制CXCR2配体KC（CXCL1）和MIP-2（CXCL2），这对于中性粒细胞募集至关重要，我们进一步表明，这些趋化因子的早期恢复会在流感后的细菌清除率中逆转。我们随后的研究表明，IL-27是IL-12家族的杂二聚体细胞因子家族的新成员，是一种IFN调节的基因，在流感感染期间诱导，在influenza细菌pneumonia pneumonia pnefluenza pneumonia期间引起的KC和MIP2产生和中性粒细胞的负调节剂。因此，我们假设在流感感染期间，I型IFNS通过诱导IL-27的表达来介导对继发性肺炎链球菌感染的嗜中性粒细胞反应受损。为了检验这一假设，我们将进行以下目的进行研究：1。确定IL-27在I型IFN介导的IFN介导后炎后细菌性肺炎的敏感性中的作用； 2。确定IL-27抑制中性粒细胞反应的机制。使用功能获得和功能方法的丧失，拟议的研究将研究IL-27的体内作用，作为一种机制，IFN抑制早期中性粒细胞反应并损害细菌清除率。此外，我们将检查IL-27通过体内和体外方法的组合对IL-27调节嗜中性粒细胞细菌性肺炎的直接机制。这些研究的结果将提供重要的机理见解，以了解炎后细菌性肺炎期间中性粒细胞的早期反应如何受损，并进一步了解我们对细菌感染中I型IFN的作用的理解。此外，由于对FIL-27在先天免疫和感染中的作用知之甚少，因此提出的研究很可能通过提供有关IL-27如何调节中性粒细胞反应的新信息来推进该领域，尤其是在一个非常重要的临床问题的背景下。最后，鉴于流感感染的全球影响，这些研究的结果将确定IL-27是否是IFN调节的可以在治疗上操纵以逆转流感诱导肺部宿主防御损害的分子。