scholarly journals Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

2013 ◽  
Vol 81 (3) ◽  
pp. 645-652 ◽  
Author(s):  
Kirsty R. Short ◽  
Patrick C. Reading ◽  
Lorena E. Brown ◽  
John Pedersen ◽  
Brad Gilbertson ◽  
...  
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Influenza A ◽  
Pneumococcal Disease ◽  
Influenza Viruses ◽  
Dependent Manner ◽  
Proinflammatory Response ◽  
Content Type ◽  
Infant Mouse ◽  
Human Middle Ear

ABSTRACTInfluenza A virus (IAV) predisposes individuals to secondary infections with the bacteriumStreptococcus pneumoniae(the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM.

scholarly journals Increased Nasopharyngeal Bacterial Titers and Local Inflammation Facilitate Transmission of Streptococcus pneumoniae

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Kirsty R. Short ◽  
Patrick C. Reading ◽  
Nancy Wang ◽  
Dimitri A. Diavatopoulos ◽  
Odilia L. Wijburg
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Influenza A ◽  
Pneumococcal Disease ◽  
Present Report ◽  
Bacterial Load ◽  
Disease Development ◽  
Proinflammatory Response ◽  
Content Type ◽  
Infant Mouse

ABSTRACTThe transmission of the bacteriumStreptococcus pneumoniae(the pneumococcus) marks the first step toward disease development. To date, our ability to prevent pneumococcal transmission has been limited by our lack of understanding regarding the factors which influence the spread of this pathogen. We have previously developed an infant mouse model of pneumococcal transmission which was strictly dependent on influenza A virus (IAV) coinfection of both the experimentally colonized “index mice” and the naive cohoused “contact mice.” Here, we sought to use this model to further elucidate the factors which facilitateS. pneumoniaetransmission. In the present report, we demonstrate that increasing the nasopharyngeal load ofS. pneumoniaein the colonized index mice (via the depletion of neutrophils) and inducing a proinflammatory response in the naive cohoused contact mice (as demonstrated by cytokine production) facilitatesS. pneumoniaetransmission. Thus, these data provide the first insights into the factors that help mediate the spread ofS. pneumoniaethroughout the community.IMPORTANCEStreptococcus pneumoniae(the pneumococcus) is a major cause of worldwide morbidity and mortality and is a leading cause of death among children under the age of five years. Transmission ofS. pneumoniaemarks the first step toward disease development. Therefore, understanding the factors that influence the spread of pneumococci throughout the community plays an essential role in preventing pneumococcal disease. We previously developed the first reproducible infant mouse model for pneumococcal transmission and showed that coinfection with influenza virus facilitates the spread ofS. pneumoniae. Here, we show that increasing the bacterial load in the nasal cavity of colonized individuals as well as inducing an inflammatory response in naive “contact cases” facilitates the spread of pneumococci. Therefore, this study helps to identify the factors which must be inhibited in order to successfully prevent pneumococcal disease.

scholarly journals Expression of Cytokine and Chemokine Genes by Human Middle Ear Epithelial Cells Induced by Influenza A Virus and Streptococcus pneumoniae Opacity Variants

2003 ◽  
Vol 71 (8) ◽  
pp. 4289-4296 ◽  
Author(s):  
H. H. Tong ◽  
J. P. Long ◽  
P. A. Shannon ◽  
T. F. DeMaria
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mrna Expression ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Primary Cultures ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Tnf Α ◽  
Human Middle Ear

ABSTRACT Real-time PCR and enzyme-linked immunosorbent assay were used to evaluate the ability of influenza A virus and Streptococcus pneumoniae opacity variants, either alone or in combination, to induce cytokine and chemokine genes in primary cultures of human middle ear epithelial (HMEE) cells. Following treatment with influenza A virus, the induction of gene expression, which occurred in a dose- and time-dependent manner, was strong for macrophage inflammatory protein 1α (MIP-1α) and MIP-1β; moderate for tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8; and weak for IL-1β and monocyte chemotactic peptide 1 (MCP-1). Except for TNF-α, all the gene products were detected in the cell culture supernatants. In contrast, infection of HMEE cells with S. pneumoniae alone induced low levels of mRNA expression of MIP-1α and MIP-1β and did not significantly induce the transcription of the other cytokines and chemokines examined. However, both S. pneumoniae opacity variants increased mRNA expression of MIP-1α, MIP-1β, IL-6, and MCP-1 in HMEE cells activated by a prior influenza A virus infection compared to levels in cells treated with either agent alone. Up-regulation of IL-6, IL-8, and MCP-1 mRNA expression and production by the virus in combination with opaque S. pneumoniae was two- to threefold higher than that induced by the virus combined with the transparent S. pneumoniae variant. These data indicate that the activation of HMEE cells by influenza A virus enhances the induction of cytokine and chemokine gene transcripts by S. pneumoniae and that this effect appears to be most pronounced when S. pneumoniae is in the opaque phase.

Alteration of gene expression in human middle ear epithelial cells induced by influenza A virus and its implication for the pathogenesis of otitis media

2004 ◽  
Vol 37 (4) ◽  
pp. 193-204 ◽  
Author(s):  
Hua Hua Tong ◽  
James P. Long ◽  
Daneng Li ◽  
Thomas F. DeMaria
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Otitis Media ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Human Middle Ear

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

2013 ◽  
Vol 82 (1) ◽  
pp. 364-370 ◽  
Author(s):  
Kirsty R. Short ◽  
Maren von Köckritz-Blickwede ◽  
Jeroen D. Langereis ◽  
Keng Yih Chew ◽  
Emma R. Job ◽  
...  
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Influenza A ◽  
Bacterial Load ◽  
Neutrophil Extracellular Trap ◽  
Content Type ◽  
Middle Ear Infection ◽  
Host Inflammatory Response ◽  
Insight Into ◽  
Bacterial Outgrowth

ABSTRACTOtitis 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) andStreptococcus 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 ofS. pneumoniaein 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.

scholarly journals Modified Lipooligosaccharide Structure Protects Nontypeable Haemophilus influenzae from IgM-Mediated Complement Killing in Experimental Otitis Media

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
Jeroen D. Langereis ◽  
Kim Stol ◽  
Elke K. Schweda ◽  
Brigitte Twelkmeyer ◽  
Hester J. Bootsma ◽  
...  
Keyword(s):  
Mouse Model ◽  
Haemophilus Influenzae ◽  
Molecular Mechanism ◽  
Otitis Media ◽  
Middle Ear ◽  
Crucial Role ◽  
Influenza A ◽  
Gram Negative ◽  
Content Type ◽  
Complement Resistance

ABSTRACTNontypeableHaemophilus influenzae(NTHi) is a Gram-negative, human-restricted pathogen. Although this bacterium typically colonizes the nasopharynx in the absence of clinical symptoms, it is also one of the major pathogens causing otitis media (OM) in children. Complement represents an important aspect of the host defense against NTHi. In general, NTHi is efficiently killed by complement-mediated killing; however, various resistance mechanisms have also evolved. We measured the complement resistance of NTHi isolates isolated from the nasopharynx and the middle ear fluids of OM patients. Furthermore, we determined the molecular mechanism of NTHi complement resistance. Complement resistance was strongly increased in isolates from the middle ear, which correlated with decreased binding of IgM. We identified a crucial role for the R2866_0112 gene in complement resistance. Deletion of this gene altered the lipooligosaccharide (LOS) composition of the bacterium, which increased IgM binding and complement-mediated lysis. In a novel mouse model of coinfection with influenza virus, we demonstrate decreased virulence for the R2866_0112 deletion mutant. These findings identify a mechanism by which NTHi modifies its LOS structure to prevent recognition by IgM and activation of complement. Importantly, this mechanism plays a crucial role in the ability of NTHi to cause OM.IMPORTANCENontypeableHaemophilus influenzae(NTHi) colonizes the nasopharynx of especially young children without any obvious symptoms. However, NTHi is also a major pathogen in otitis media (OM), one of the most common childhood infections. Although this pathogen is often associated with OM, the mechanism by which this bacterium is able to cause OM is largely unknown. Our study addresses a key biological question that is highly relevant for child health: what is the molecular mechanism that enables NTHi to cause OM? We show that isolates collected from the middle ear fluid exhibit increased complement resistance and that the lipooligosaccharide (LOS) structure determines IgM binding and complement activation. Modification of the LOS structure decreased NTHi virulence in a novel NTHi-influenza A virus coinfection OM mouse model. Our findings may also have important implications for other Gram-negative pathogens harboring LOS, such asNeisseria meningitidis,Moraxella catarrhalis, andBordetella pertussis.

scholarly journals Niche- and Gender-Dependent Immune Reactions in Relation to the Microbiota Profile in Pediatric Patients with Otitis Media with Effusion

2020 ◽  
Vol 88 (10) ◽  
Author(s):  
Frida Enoksson ◽  
Alicia Ruiz Rodriguez ◽  
Chikondi Peno ◽  
Carlos Balcazar Lopez ◽  
Fredrik Tjernström ◽  
...  
Keyword(s):  
Immune Responses ◽  
Otitis Media ◽  
Middle Ear ◽  
Inflammatory Mediators ◽  
Otitis Media With Effusion ◽  
Bacterial Species ◽  
Microbial Community Composition ◽  
Low Grade ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACT Otitis media with effusion (OME) is a common inflammatory disease that primarily affects children. OME is defined as a chronic low-grade inflammation of the middle ear (ME), without any signs of infection and with effusion persisting in the ME for more than 3 months. The precise pathogenesis is, however, not fully understood. Here, we comprehensively characterized and compared the host immune responses (inflammatory cells and mediators) and the overall microbial community composition (microbiota) present in matched middle ear effusion (MEE) samples, external ear canal (EEC) lavages, and nasopharynx (NPH) samples from children with OME. Female patients had significantly increased percentages of T lymphocytes and higher levels of a wide array of inflammatory mediators in their MEE compared to that of male patients, which were unrelated to microbiota composition. The relative abundances of identified microorganisms were strongly associated with their niche of origin. Furthermore, specific inflammatory mediators were highly correlated with certain bacterial species. Interestingly, some organisms displayed a niche-driven inflammation pattern in which presence of Haemophilus spp. and Corynebacterium propinquum in MEE was accompanied by proinflammatory mediators, whereas their presence in NPH was accompanied by anti-inflammatory mediators. For Turicella and Alloiococcus, we found exactly the opposite results, i.e., an anti-inflammatory profile when present in MEE, whereas their presence in the the NPH was accompanied by a proinflammatory profile. Together, our results indicate that immune responses in children with OME are highly niche- and microbiota-driven, but gender-based differences were also observed, providing novel insight into potential pathogenic mechanisms behind OME.

scholarly journals Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

2019 ◽  
Vol 20 (24) ◽  
pp. 6261
Author(s):  
Min Guo ◽  
Jiawei Ni ◽  
Jie Yu ◽  
Jing Jin ◽  
Lingman Ma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Benzoic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Influenza Viruses ◽  
Drug Candidate ◽  
Dependent Manner ◽  
Drug Resistant

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

scholarly journals Two DHH Subfamily 1 Proteins Contribute to Pneumococcal Virulence and Confer Protection against Pneumococcal Disease

2011 ◽  
Vol 79 (9) ◽  
pp. 3697-3710 ◽  
Author(s):  
L. E. Cron ◽  
K. Stol ◽  
P. Burghout ◽  
S. van Selm ◽  
E. R. Simonetti ◽  
...  
Keyword(s):  
Otitis Media ◽  
Pneumococcal Disease ◽  
Capsular Polysaccharide ◽  
Pneumococcal Infection ◽  
Bacterial Pathogen ◽  
Protein Vaccine ◽  
Double Knockout ◽  
Content Type ◽  
Knockout Mutants ◽  
Different Strains

ABSTRACTStreptococcus pneumoniaeis an important human bacterial pathogen, causing such infections as pneumonia, meningitis, septicemia, and otitis media. Current capsular polysaccharide-based conjugate vaccines protect against a fraction of the over 90 serotypes known, whereas vaccines based on conserved pneumococcal proteins are considered promising broad-range alternatives. The pneumococcal genome encodes two conserved proteins of an as yet unknown function, SP1298 and SP2205, classified as DHH (Asp-His-His) subfamily 1 proteins. Here we examined their contribution to pneumococcal pathogenesis using single and double knockout mutants in three different strains: D39, TIGR4, and BHN100. Mutants lacking both SP1298 and SP2205 were severely impaired in adherence to human epithelial Detroit 562 cells. Importantly, the attenuated phenotypes were restored upon genetic complementation of the deleted genes. Single and mixed mouse models of colonization, otitis media, pneumonia, and bacteremia showed that bacterial loads in the nasopharynx, middle ears, lungs, and blood of mice infected with the mutants were significantly reduced from those of wild-type-infected mice, with an apparent additive effect upon deletion of both genes. Minor strain-specific phenotypes were observed, i.e., deletion of SP1298 affected host-cell adherence in BHN100 only, and deletion of SP2205 significantly attenuated virulence in lungs and blood in D39 and BHN100 but not TIGR4. Finally, subcutaneous vaccination with a combination of both DHH subfamily 1 proteins conferred protection to nasopharynx, lungs, and blood of mice infected with TIGR4. We conclude that SP1298 and SP2205 play a significant role at several stages of pneumococcal infection, and importantly, these proteins are potential candidates for a multicomponent protein vaccine.

scholarly journals Moraxella catarrhalis Might Be More Common than Expected in Acute Otitis Media in Young Finnish Children

2016 ◽  
Vol 54 (9) ◽  
pp. 2373-2379 ◽  
Author(s):  
Saara Sillanpää ◽  
Sami Oikarinen ◽  
Markku Sipilä ◽  
Lenka Kramna ◽  
Markus Rautiainen ◽  
...  
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Moraxella Catarrhalis ◽  
Acute Otitis Media ◽  
Pcr Analysis ◽  
Considerable Proportion ◽  
Bacterial Dna ◽  
Content Type ◽  
Conventional Culture

According to studies based on bacterial cultures of middle ear fluids,Streptococcus pneumoniae,Haemophilus influenzae, andMoraxella catarrhalishave been the most common pathogens in acute otitis media. However, bacterial culture can be affected by reduced viability or suboptimal growth of bacteria. PCR detects bacterial DNA from samples with greater sensitivity than culture. In the present study, we analyzed the middle ear pathogens with both conventional culture and semiquantitative real-time PCR in 90 middle ear fluid samples obtained from children aged 5 to 42 months during acute otitis media episodes. Samples were tested for the presence ofS. pneumoniae,H. influenzae,M. catarrhalis,Alloiococcusotitidis,Staphylococcus aureus, andPseudomonas aeruginosa. One or more bacterial pathogens were detected in 42 (47%) samples with culture and in 69 (77%) samples with PCR. According to PCR analysis,M. catarrhalisresults were positive in 42 (47%) samples,H. influenzaein 30 (33%),S. pneumoniaein 27 (30%),A. otitidisin 6 (6.7%),S. aureusin 5 (5.6%), andP. aeruginosain 1 (1.1%). Multibacterial etiology was seen in 34 (38%) samples, andM. catarrhaliswas detected in most (85%) of those cases. Fifteen signals forM. catarrhaliswere strong, suggesting a highly probable etiological role of the pathogen. In conclusion, even thoughM. catarrhalisis often a part of mixed flora in acute otitis media, a considerable proportion of cases may be primarily attributable to this pathogen.

scholarly journals Bacterial Sinusitis and Otitis Media following Influenza Virus Infection in Ferrets

2006 ◽  
Vol 74 (5) ◽  
pp. 2562-2567 ◽  
Author(s):  
Ville T. Peltola ◽  
Kelli L. Boyd ◽  
Julie L. McAuley ◽  
Jerold E. Rehg ◽  
Jonathan A. McCullers
Keyword(s):  
Influenza Virus ◽  
Otitis Media ◽  
Influenza A ◽  
Bacterial Colonization ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Influenza B ◽  
Complication Rates ◽  
Pneumococcal Infections

ABSTRACT Streptococcus pneumoniae is the leading cause of otitis media, sinusitis, and pneumonia. Many of these infections result from antecedent influenza virus infections. In this study we sought to determine whether the frequency and character of secondary pneumococcal infections differed depending on the strain of influenza virus that preceded bacterial challenge. In young ferrets infected with influenza virus and then challenged with pneumococcus, influenza viruses of any subtype increased bacterial colonization of the nasopharynx. Nine out of 10 ferrets infected with H3N2 subtype influenza A viruses developed either sinusitis or otitis media, while only 1 out of 11 ferrets infected with either an H1N1 influenza A virus or an influenza B virus did so. These data may partially explain why bacterial complication rates are higher during seasons when H3N2 viruses predominate. This animal model will be useful for further study of the mechanisms that underlie viral-bacterial synergism.

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