Mechanisms of impaired neutrophil responses in postinfluenza bacterial pneumonia

流感后细菌性肺炎中性粒细胞反应受损的机制

• 批准号: 8677960
• 负责人: Jane C Deng
• 金额: $ 37.73万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677960
• 关键词: Address; Alveolar Macrophages; Animals; Anti-Bacterial Agents; Antibiotics; Antiviral Agents; Applications Grants; Bacterial Infections; Bacterial Pneumonia; Bone Marrow; CXCL1 gene; CXCL2 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; 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

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，在大流行期间死亡人数更多。继发性细菌性肺炎是流感的主要致命并发症，其发病机制尚不清楚。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，该提议的直接目标是检查I型干扰素（ifn）和IL-27在流感后肺部感染肺炎链球菌感染期间作为中性粒细胞反应的关键介质的作用，肺炎链球菌是世界范围内细菌性肺炎的最重要原因。我们发表的数据显示，在流感感染期间诱导的I型干扰素（ifn）抑制了早期中性粒细胞对继发性肺炎链球菌感染的反应，导致细菌清除受损和死亡率增加。这可归因于I型ifn介导的CXCR2配体KC （CXCL1）和MIP-2 （CXCL2）的抑制，这对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逆转了流感后细菌清除的缺陷。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ifn调控的基因，在流感感染期间被诱导，并在流感后细菌性肺炎期间作为KC和MIP2产生和中性粒细胞募集的负调节因子。因此，我们假设在流感感染期间，I型ifn通过诱导IL-27的表达介导中性粒细胞对继发性肺炎链球菌感染反应的损害。为了验证这一假设，我们将进行以下目的的研究：探讨IL-27在I型ifn介导的流感后细菌性肺炎易感性中的作用；和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丧失的方法，拟议的研究将检查IL-27在体内的作用，通过ifn抑制早期中性粒细胞反应和损害细菌清除的机制。此外，我们将通过体内和体外结合的方法研究IL-27调节中性粒细胞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流感后细菌性肺炎期间早期中性粒细胞反应受损的机制提供重要的见解，并进一步了解I型ifn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会通过提供有关IL-27如何调节中性粒细胞反应的新信息来推进该领域，特别是在一个非常重要的临床问题的背景下。最后，鉴于流感感染的持续全球影响，这些研究的结果将确定IL-27是否受干扰素调节