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      Enhanced IL-1β production is mediated by a TLR2-MYD88-NLRP3 signaling axis during coinfection with influenza A virus and Streptococcus pneumoniae

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          Abstract

          Viral-bacterial coinfections, such as with influenza A virus and Streptococcus pneumoniae ( S. p.), are known to cause severe pneumonia. It is well known that the host response has an important role in disease. Interleukin-1β (IL-1β) is an important immune signaling cytokine responsible for inflammation and has been previously shown to contribute to disease severity in numerous infections. Other studies in mice indicate that IL-1β levels are dramatically elevated during IAV- S. p. coinfection. However, the regulation of IL-1β during coinfection is unknown. Here, we report the NLRP3 inflammasome is the major inflammasome regulating IL-1β activation during coinfection. Furthermore, elevated IL-1β mRNA expression is due to enhanced TLR2-MYD88 signaling, which increases the amount of pro-IL-1β substrate for the inflammasome to process. Finally, NLRP3 and high IL-1β levels were associated with increased bacterial load in the brain. Our results show the NLRP3 inflammasome is not protective during IAV- S. p. coinfection.

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          Most cited references36

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          The co-pathogenesis of influenza viruses with bacteria in the lung.

          Concern that a highly pathogenic virus might cause the next influenza pandemic has spurred recent research into influenza and its complications. Bacterial superinfection in the lungs of people suffering from influenza is a key element that promotes severe disease and mortality. This co-pathogenesis is characterized by complex interactions between co-infecting pathogens and the host, leading to the disruption of physical barriers, dysregulation of immune responses and delays in a return to homeostasis. The net effect of this cascade can be the outgrowth of the pathogens, immune-mediated pathology and increased morbidity. In this Review, advances in our understanding of the underlying mechanisms are discussed, and the key questions that will drive the field forwards are articulated.
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            Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection.

            Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-gamma, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.
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              Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice.

              Influenza-related complications continue to be a major cause of mortality worldwide. Due to unclear mechanisms, a substantial number of influenza-related deaths result from bacterial superinfections, particularly secondary pneumococcal pneumonia. Here, we report what we believe to be a novel mechanism by which influenza-induced type I IFNs sensitize hosts to secondary bacterial infections. Influenza-infected mice deficient for type I IFN-alpha/beta receptor signaling (Ifnar-/- mice) had improved survival and clearance of secondary Streptococcus pneumoniae infection from the lungs and blood, as compared with similarly infected wild-type animals. The less effective response in wild-type mice seemed to be attributable to impaired production of neutrophil chemoattractants KC (also known as Cxcl1) and Mip2 (also known as Cxcl2) following secondary challenge with S. pneumoniae. This resulted in inadequate neutrophil responses during the early phase of host defense against secondary bacterial infection. Indeed, influenza-infected wild-type mice cleared secondary pneumococcal pneumonia after pulmonary administration of exogenous KC and Mip2, whereas neutralization of Cxcr2, the common receptor for KC and Mip2, reversed the protective phenotype observed in Ifnar-/- mice. These data may underscore the importance of the type I IFN inhibitory pathway on CXC chemokine production. Collectively, these findings highlight what we believe to be a novel mechanism by which the antiviral response to influenza sensitizes hosts to secondary bacterial pneumonia.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 February 2019
                2019
                : 14
                : 2
                : e0212236
                Affiliations
                [1 ] Department of Biology, Missouri State University, Springfield, Missouri, United States of America
                [2 ] Department of Pathology, Cox Medical Center South, Springfield, Missouri, United States of America
                [3 ] Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States of America
                [4 ] Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, United States of America
                Virginia Polytechnic Institute and State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                [¤]

                Current address: Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas, United States of America

                Author information
                http://orcid.org/0000-0002-7237-6002
                http://orcid.org/0000-0002-6586-004X
                Article
                PONE-D-18-33088
                10.1371/journal.pone.0212236
                6386446
                30794604
                e4b847a8-0abc-4121-8168-9e15db3b971e
                © 2019 Rodriguez et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 November 2018
                : 29 January 2019
                Page count
                Figures: 4, Tables: 1, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R56 AI125324
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: K25 AI00946
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100012524, American Lebanese Syrian Associated Charities;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100012524, American Lebanese Syrian Associated Charities;
                Award ID: JAM
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010923, Missouri State University;
                Award ID: F07314
                Award Recipient :
                This work was supported by National Institutes of Health Grants R56 AI125324 (AMS) and K25 AI00946 (AMS), the American Lebanese Syrian Associated Charities (JAM and TDK) and Missouri State University Grant F07314 (CRL). AMS received salary support from the National Institutes of Health grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The results publish here do not necessarily reflect the views of the funding agencies.
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