Mechanisms of impaired neutrophil responses in postinfluenza bacterial pneumonia

描述(申请人提供)：流感是一个巨大的全球公共卫生威胁，每年导致多达50万人死亡，在大流行期间还会有更多人死亡。继发性细菌性肺炎是流感的主要致命性并发症，其发病机制尚不清楚。我研究的长期目标是揭开流感导致肺部抗菌宿主防御免疫抑制的机制，这项提议的近期目标是研究I型干扰素(IFN)和IL-27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的作用，这是全球细菌性肺炎的最重要原因。我们已发表的数据显示，在流感感染期间诱导的I型干扰素(IFN)抑制了针对继发性肺炎链球菌感染的早期中性粒细胞反应，导致细菌清除受损和死亡率增加。这归因于I型干扰素介导的CXCR2配体KC(CXCL1)和MIP-2(CXCL2)的抑制，这两个配体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可以逆转流感后细菌清除方面的缺陷。我们随后的研究表明，IL-27是IL-12异二聚体细胞因子家族的新成员，是一种受干扰素调节的基因，在流感感染期间诱导，并在流感后细菌性肺炎期间对KC和MIP2的产生以及中性粒细胞募集起负调控作用。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对继发性肺炎链球菌感染的反应受损。为了验证这一假设，我们将进行以下研究：1.确定IL-27在I型干扰素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。利用功能获得和功能丧失的方法，拟议的研究将检验IL-27在体内的作用，作为IFN抑制早期中性粒细胞反应和损害细菌清除的机制。此外，我们将采用体内和体外相结合的方法，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如何受损提供重要的机制见解，并进一步了解I型IFN在细菌感染中的作用。此外，由于对IL-27在先天免疫和感染中的作用知之甚少，建议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动该领域的发展，特别是在一个非常重要的临床问题的背景下。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是否是受干扰素调控的 可在治疗上被操纵以逆转流感引起的肺宿主防御功能受损的分子。

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.