Mechanisms of impaired neutrophil responses in postinfluenza bacterial pneumonia

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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. PUBLIC HEALTH RELEVANCE: Bacterial superinfections following influenza infections are a leading cause of morbidity and mortality worldwide, and a deadly complication that needs to be addressed given the constant threat of an influenza pandemic. We have found that type I interferons, which are a family of proteins that are important during viral infections, are responsible for inhibiting lung recruitment of neutrophils, a type of white blood cell that is critcal for fighting bacterial infections. Using an experimental model of sequential influenza and bacterial infection, we propose in this grant to determine whether type I interferon-mediated regulation of the interleukin-27 pathway is the mechanism responsible for this phenomenon. Hopefully, these studies will aid in the development of novel immune-based therapies targeting this pathway to reverse the immunosuppressive effects of influenza.