Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

Short, Kirsty R.; Reading, Patrick C.; Brown, Lorena E.; Pedersen, John; Gilbertson, Brad; Job, Emma R.; Edenborough, Kathryn M.; Habets, Marrit N.; Zomer, Aldert; Hermans, Peter W. M.; Diavatopoulos, Dimitri A.; Wijburg, Odilia L. C.

doi:10.1128/iai.01278-12

Cited by 62 publications

(76 citation statements)

References 34 publications

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“…Hemagglutinin (H)-3 subtypes of influenza virus replicate to high titer in the middle ear of mice, and the ensuing inflammatory response promotes replication of S. pneumoniae at this site. 181 This effect is dependent on hemagglutinin subtype, with greater replication of H3 than H1 subtypes in the middle ear, 181 and on anatomic site, with no differences between hemagglutinin subtypes in the nasopharynx. 133 Although influenza in mice is not equivalent to viral infections of the cattle, the concept that virus-induced inflammation can trigger bacterial replication may be informative.…”

Section: Effects Of Predisposing Factors On Bacterial Colonization Ofmentioning

confidence: 99%

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

Caswell

2013

Vet Pathol

108

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The respiratory system is well defended against inhaled bacteria by a dynamic system of interacting layers, including mucociliary clearance, host defense factors including antimicrobial peptides in the epithelial lining fluid, proinflammatory responses of the respiratory epithelium, resident alveolar macrophages, and recruited neutrophils and monocytes. Nevertheless, these manifold defenses are susceptible to failure as a result of stress, glucocorticoids, viral infections, abrupt exposure to cold air, and poor air quality. When some of these defenses fail, the lung can be colonized by bacterial pathogens that are equipped to evade the remaining defenses, resulting in the development of pneumonia. This review considers the mechanisms by which these predisposing factors compromise the defenses of the lung, with a focus on the development of bacterial pneumonia in cattle and supplemented with advances based on mouse models and the study of human disease. Deepening our understanding of how the respiratory defenses fail is expected to lead to interventions that restore these dynamic immune responses and prevent disease.

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Section: Effects Of Predisposing Factors On Bacterial Colonization Ofmentioning

confidence: 99%

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

Caswell

2013

Vet Pathol

108

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“…Briefly, cell monolayers were infected, and then RNA extraction and DNase treatment were performed as described above. The levels of vRNA and mRNA for the matrix (M), NP, HA, NA, polymerase acidic protein (PA), polymerase B subunit 1 (PB1), PB2, and nonstructural protein (NS) genes were determined via qRT-PCR using SYBR green-based chemistry, as described previously (16). Briefly, cDNA was synthesized using the Omniscript reverse transcriptase kit (Qiagen, USA) according to the manufacturer's instructions with oligo(dT)s (Roche, Australia) for mRNA or Uni12 primer (17) for vRNA.…”

Section: Virus Infection Assaysmentioning

confidence: 99%

Infection of Mouse Macrophages by Seasonal Influenza Viruses Can Be Restricted at the Level of Virus Entry and at a Late Stage in the Virus Life Cycle

Londrigan

Short

et al. 2015

J Virol

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Airway epithelial cells are susceptible to infection with seasonal influenza A viruses (IAV), resulting in productive virus replication and release. Macrophages (M⌽) are also permissive to IAV infection; however, virus replication is abortive. Currently, it is unclear how productive infection of M⌽ is impaired or the extent to which seasonal IAV replicate in M⌽. Herein, we compared mouse M⌽ and epithelial cells for their ability to support genomic replication and transcription, synthesis of viral proteins, assembly of virions, and release of infectious progeny following exposure to genetically defined IAV. We confirm that seasonal IAV differ in their ability to utilize cell surface receptors for infectious entry and that this represents one level of virus restriction. Following virus entry, we demonstrate synthesis of all eight segments of genomic viral RNA (vRNA) and mRNA, as well as seven distinct IAV proteins, in IAV-infected mouse M⌽. Although newly synthesized hemagglutinin (HA) and neuraminidase (NA) glycoproteins are incorporated into the plasma membrane and expressed at the cell surface, electron microscopy confirmed that virus assembly was defective in IAV-infected M⌽, defining a second level of restriction late in the virus life cycle. IMPORTANCE Seasonal influenza A viruses (IAV) and highly pathogenic avian influenza viruses (HPAI) infect macrophages, but only HPAIreplicate productively in these cells. Herein, we demonstrate that impaired virus uptake into macrophages represents one level of restriction limiting infection by seasonal IAV. Following uptake, seasonal IAV do not complete productive replication in macrophages, representing a second level of restriction. Using murine macrophages, we demonstrate that productive infection is blocked late in the virus life cycle, such that virus assembly is defective and newly synthesized virions are not released. These studies represent an important step toward identifying host-encoded factors that block replication of seasonal IAV, but not HPAI, in macrophages. In humans, infection with seasonal influenza A viruses (IAV) is generally restricted to the respiratory tract. IAV infection of airway epithelial cells (AEC) is initiated following recognition of cell surface sialic acid (SIA) by the viral hemagglutinin (HA) glycoprotein (reviewed in reference 1). In addition to HA-SIA binding, it is likely that particular membrane-associated glycoproteins and/or glycolipids facilitate virus entry into AEC; however, the identity of such an entry receptor(s) is currently unknown. IAV infection of AEC results in productive virus replication, characterized by synthesis of viral RNA (vRNA) and mRNA, production of viral proteins, virion assembly, and budding of viral progeny from the surfaces of infected cells. Productive infection of AEC results in amplification of IAV in the airways, promoting virus dissemination and disease.In addition to AEC, macrophages (M⌽) are one of the first cells in the respiratory tract to detect and respond to IAV. As for AEC, binding ...

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“…In clinical cases and experimental models, infection with IAV facilitates the replication of S. pneumoniae in the middle ear (3)(4)(5)(6)(7)(8). Using an infant mouse model of OM (designed to mimic the underdeveloped immune system of children), we have previously demonstrated that the development of pneumococcal OM in coinfected mice was due to the inflammation induced by IAV in the middle ear (3,8). However, the mechanisms by which the host inflammatory response mediates secondary pneumococcal OM remain undefined.…”

mentioning

confidence: 99%

Antibodies Mediate Formation of Neutrophil Extracellular Traps in the Middle Ear and Facilitate Secondary Pneumococcal Otitis Media

et al. 2014

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g Otitis media (OM) (a middle ear infection) is a common childhood illness that can leave some children with permanent hearing loss. OM can arise following infection with a variety of different pathogens, including a coinfection with influenza A virus (IAV) and Streptococcus pneumoniae (the pneumococcus). We and others have demonstrated that coinfection with IAV facilitates the replication of pneumococci in the middle ear. Specifically, we used a mouse model of OM to show that IAV facilitates the outgrowth of S. pneumoniae in the middle ear by inducing middle ear inflammation. Here, we seek to understand how the host inflammatory response facilitates bacterial outgrowth in the middle ear. Using B cell-deficient infant mice, we show that antibodies play a crucial role in facilitating pneumococcal replication. We subsequently show that this is due to antibody-dependent neutrophil extracellular trap (NET) formation in the middle ear, which, instead of clearing the infection, allows the bacteria to replicate. We further demonstrate the importance of these NETs as a potential therapeutic target through the transtympanic administration of a DNase, which effectively reduces the bacterial load in the middle ear. Taken together, these data provide novel insight into how pneumococci are able to replicate in the middle ear cavity and induce disease.

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Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

Cited by 62 publications

References 34 publications

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

Failure of Respiratory Defenses in the Pathogenesis of Bacterial Pneumonia of Cattle

Infection of Mouse Macrophages by Seasonal Influenza Viruses Can Be Restricted at the Level of Virus Entry and at a Late Stage in the Virus Life Cycle

Antibodies Mediate Formation of Neutrophil Extracellular Traps in the Middle Ear and Facilitate Secondary Pneumococcal Otitis Media

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