Mechanisms of impaired neutrophil responses in postinfluenza bacterial pneumonia

描述（由申请人提供）：流感是全球范围内一种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，其机制仍不清楚。我的研究的长期目标是解开机制，负责流感诱导的免疫抑制的抗菌宿主防御在肺部，与本提案的直接目标是检查的作用，I型干扰素（IFN）和IL-27作为中性粒细胞反应的关键介质在流感后肺部感染肺炎链球菌，这是最重要的原因细菌性肺炎全球。我们发表的数据表明，在流感感染过程中诱导的I型干扰素（IFN）抑制了早期中性粒细胞对继发性S。肺炎感染，导致细菌清除受损和死亡率增加。这是由于I型IFN介导的抑制CXCR 2配体，KC（CXCL 1）和MIP-2（CXCL 2），这是至关重要的中性粒细胞招聘，我们还表明，这些趋化因子的早期恢复逆转流感后细菌清除的缺陷。我们随后的研究表明，IL-27，异源二聚体细胞因子的IL-12家族的新成员，是一种IFN调节的基因，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MIP 2产生和中性粒细胞募集的负调节剂。因此，我们假设在流感感染期间，I型干扰素介导中性粒细胞对继发性S。通过诱导IL-27的表达来抑制肺炎链球菌感染。为了验证这一假设，我们将进行以下目的的研究：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;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方法，拟议的研究将检查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，我们将研究IL-27通过体内和体外方法的组合调节中性粒细胞对流感后细菌性肺炎的反应的直接机制。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，以及进一步了解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通过提供关于IL-27如何调节中性粒细胞应答的新信息来推进该领域，特别是在高度重要的临床问题的背景下。最后，考虑到流感感染的持续全球影响，这些研究的结果将确定IL-27是否是IFN-γ调节的。 分子，其可以在治疗上被操纵以逆转流感诱导的肺宿主防御的损害。

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.