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 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 The NS1 Protein of Influenza A Virus Blocks RIG-I-Mediated Activation of the Noncanonical NF-κB Pathway and p52/RelB-Dependent Gene Expression in Lung Epithelial Cells

2012 ◽  
Vol 86 (18) ◽  
pp. 10211-10217 ◽  
Author(s):  
Andrea Rückle ◽  
Emanuel Haasbach ◽  
Ilkka Julkunen ◽  
Oliver Planz ◽  
Christina Ehrhardt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Influenza A Virus ◽  
Influenza A ◽  
Target Gene ◽  
Lung Epithelial Cells ◽  
Ns1 Protein ◽  
Antiviral Immune Response ◽  
Lung Epithelial ◽  
Infected Cells

Influenza A virus (IAV) infection of epithelial cells activates NF-κB transcription factors via the canonical NF-κB signaling pathway, which modulates both the antiviral immune response and viral replication. Since almost nothing is known so far about a function of noncanonical NF-κB signaling after IAV infection, we tested infected cells for activation of p52 and RelB. We show that the viral NS1 protein strongly inhibits RIG-I-mediated noncanonical NF-κB activation and expression of the noncanonical target gene CCL19.

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.

Experimental otitis media after nasal inoculation of Streptococcus pneumoniae and influenza A virus in chinchillas

1980 ◽  
Vol 30 (2) ◽  
pp. 445-450
Author(s):  
G S Giebink ◽  
I K Berzins ◽  
S C Marker ◽  
G Schiffman
Keyword(s):  
Streptococcus Pneumoniae ◽  
Otitis Media ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Acute Otitis Media ◽  
Aerobic Bacteria ◽  
Middle Ear Effusion ◽  
Respiratory Viral Infection ◽  
Ear Effusion

Otitis media developed in 67% of chinchillas inoculated intranasally with type 7 Streptococcus pneumoniae and influenza A virus. Only 4% of chinchillas inoculated with influenza alone and 21% of chinchillas inoculated with S. pneumoniae alone developed otitis media. Among the chinchillas that developed otitis media after inoculation with both pneumococcus and influenza, 73% of the affected ears contained effusion, and 27% of the affected ears showed tympanic membrane inflammation without middle ear effusion obtained on paracentesis. Although a majority of the ears with effusion yielded S. pneumoniae on culture, one-third of the effusions were sterile for aerobic bacteria. This model resembles conditions accompanying otitis media in humans and suggests that respiratory viral infection contributes significantly to the pathogenesis of acute otitis media.

Otologic and Systemic Manifestations of Experimental Influenza a Virus Infection in the Ferret

1995 ◽  
Vol 112 (4) ◽  
pp. 572-578 ◽  
Author(s):  
Craig A. Buchman ◽  
J. Douglas Swarts ◽  
James T. Seroky ◽  
Nicholas Panagiotou ◽  
Frederick Hayden ◽  
...  
Keyword(s):  
Otitis Media ◽  
Influenza A Virus ◽  
Eustachian Tube ◽  
Middle Ear ◽  
Influenza A ◽  
Upper Respiratory Tract Infections ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Influenza A Virus Infection ◽  
Tract Infections

In an effort to further validate an animal model and to better define the mechanisms relating viral upper respiratory tract infections and acute otitis media, we infected 10 ferrets intranasally with influenza A virus. Infection was monitored by cultures and antibody titers, illness was monitored by signs and temperatures, and otologic complications were monitored by otoscopy, tympanometry, and eustachian tube function testing. All animals became infected. Forced-response test results showed progressive increases in the passive function variables after inoculation. Inflation-deflation test results documented progressive impairment of active tubal function, which was accompanied by the development of middle ear underpressures. No otitis media was seen. The results suggest that influenza A virus infection results in progressive, subtotal occlusion of the eustachian tube lumen, which compromises the ventilatory function of the tube, thereby promoting the development of middle ear underpressures. These findings support the hypothesized pathophysiologic relationship between viral upper respiratory tract infections, eustachian tube dysfunction, middle ear underpressures, and acute otitis media. Given these pathophysiologic changes and previously documented physiologic similarities to the eustachian tube-middle ear system of human beings, we conclude that the ferret represents an appropriate animal model for studying the pathogenic processes related to viral upper respiratory tract infections, eustachian tube dysfunction, and otitis media and for testing of potential prophylactic and therapeutic regimens.

scholarly journals Comparison of Alteration of Cell Surface Carbohydrates of the Chinchilla Tubotympanum and Colonial Opacity Phenotype of Streptococcus pneumoniae during Experimental Pneumococcal Otitis Media with or without an Antecedent Influenza A Virus Infection

2002 ◽  
Vol 70 (8) ◽  
pp. 4292-4301 ◽  
Author(s):  
H. H. Tong ◽  
I. Grants ◽  
X. Liu ◽  
T. F. DeMaria
Keyword(s):  
Streptococcus Pneumoniae ◽  
Virus Infection ◽  
Cell Surface ◽  
Otitis Media ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Expression Patterns ◽  
Influenza A Virus Infection ◽  
Surface Carbohydrates

ABSTRACT Experimental and clinical studies suggest that influenza A virus promotes Streptococcus pneumoniae-induced otitis media; however, the mechanism underlying this synergistic interaction has not been completely defined. In this study, glycoconjugate expression patterns were evaluated on the cell surface in the chinchilla eustachian tube (ET) lumen of a cohort challenged intranasally (i.n.) with S. pneumoniae type 6A, which is predominantly transparent and a cohort with an antecedent influenza A virus infection, followed by i.n. inoculation with S. pneumoniae. The labeling patterns obtained with six lectin probes revealed that the binding of Bandeiraea simplicifolia lectin II, succinylated wheat germ agglutinin, and peanut agglutinin were significantly increased in the lumenal surface of the ET in the cohort infected with both pathogens compared to the cohort inoculated with only S. pneumoniae, which indicated that N-acetylglucosamine (GlcNAc) and d-galactose residues were exposed. A significant decreased labeling with Sambucus nigra agglutinin in the combined influenza A virus and pneumococcus infection cohort suggested that there were few sialic acid residues remaining in the ET epithelium. In addition, the colonial opacity of S. pneumoniae during the disease course was examined. The opaque phenotype was predominant among the pneumococcus isolates from the middle-ear fluid in the cohort infected with the both pathogens. Together, these data suggest that the synergic effect of influenza A virus and S. pneumoniae on the changes of the carbohydrate moieties in the ET epithelium and that the selection of the opaque variant may facilitate the pneumococcal invasion of the middle ear.

Immortalization of Normal Adult Human Middle Ear Epithelial Cells Using a Retrovirus Containing the E6/E7 Genes of Human Papillomavirus Type 16

2002 ◽  
Vol 111 (6) ◽  
pp. 507-517 ◽  
Author(s):  
Sung-Kyun Moon ◽  
Derald E. Brackmann ◽  
Young-Myoung chun ◽  
Haa-Yung Lee ◽  
Johng S. Rhim ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Epithelial Cells ◽  
Cell Line ◽  
Otitis Media ◽  
Middle Ear ◽  
Cell Biology ◽  
New Drugs ◽  
Epithelial Cell Line ◽  
Human Papillomavirus Type 16 ◽  
Human Middle Ear

A human middle ear epithelial cell line (HMEEC-1) was established using human papillomavirus E6/E7 genes. HMEEC-1 has remained morphologically and phenotypically stable, even after 50 passages. The cells are anchorage-dependent and nontumorigenic when injected into nude mice. This cell line thus provides a new tool for the study of normal cell biology and the pathological processes associated with the epithelial cells of the middle ear in otitis media. HMEEC-1 will also be useful in the search for new drugs and biological agents for the treatment of otitis media.

scholarly journals Effect of Influenza A Virus Infection on Nasopharyngeal Colonization and Otitis Media Induced by Transparent or Opaque Phenotype Variants of Streptococcus pneumoniae in the Chinchilla Model

2001 ◽  
Vol 69 (1) ◽  
pp. 602-606 ◽  
Author(s):  
H. H. Tong ◽  
J. N. Weiser ◽  
M. A. James ◽  
T. F. DeMaria
Keyword(s):  
Streptococcus Pneumoniae ◽  
Virus Infection ◽  
Otitis Media ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Synergistic Effects ◽  
Nasopharyngeal Colonization ◽  
Significant Difference ◽  
Influenza A Virus Infection

ABSTRACT Phase variation in the colonial opacity of Streptococcus pneumoniae has been implicated as a factor in bacterial adherence, colonization, and invasion in the pathogenesis of pneumococcal disease. Additionally, the synergistic effects of influenza A virus and S. pneumoniae in the development of otitis media (OM) have been reported. This study examined the ability of opaque or transparent S. pneumoniae from the same strain in combination with an antecedent influenza A virus infection to colonize the nasopharynx and invade the middle ear in the chinchilla model. Our data indicated that there was no significant difference in the level of nasopharyngeal colonization and induction of OM between the opaque and transparent variants unless there was a prior challenge with influenza A virus. Subsequent to influenza A virus infection, there was a significant difference between the variants in the ability to colonize and persist in the nasopharynx and middle ear. The concentrations of the opaque variant in nasopharyngeal-lavage samples and middle-ear fluid remained consistently higher than those of the transparent variant for 10 days postinoculation. Data from this study indicate that the effects of influenza A virus on the pathogenesis of experimental S. pneumoniae-induced OM differ depending on the opacity phenotype involved.

scholarly journals Influenza A Virus Alters Pneumococcal Nasal Colonization and Middle Ear Infection Independently of Phase Variation

2014 ◽  
Vol 82 (11) ◽  
pp. 4802-4812 ◽  
Author(s):  
John T. Wren ◽  
Lance K. Blevins ◽  
Bing Pang ◽  
Lauren B. King ◽  
Antonia C. Perez ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Otitis Media ◽  
Influenza A Virus ◽  
Middle Ear ◽  
Influenza A ◽  
Phase Variation ◽  
Infection Model ◽  
Ear Infection ◽  
Middle Ear Infection ◽  
Phase Variants

ABSTRACTStreptococcus pneumoniae(pneumococcus) is both a widespread nasal colonizer and a leading cause of otitis media, one of the most common diseases of childhood. Pneumococcal phase variation influences both colonization and disease and thus has been linked to the bacteria's transition from colonizer to otopathogen. Further contributing to this transition, coinfection with influenza A virus has been strongly associated epidemiologically with the dissemination of pneumococci from the nasopharynx to the middle ear. Using a mouse infection model, we demonstrated that coinfection with influenza virus and pneumococci enhanced both colonization and inflammatory responses within the nasopharynx and middle ear chamber. Coinfection studies were also performed using pneumococcal populations enriched for opaque or transparent phase variants. As shown previously, opaque variants were less able to colonize the nasopharynx.In vitro, this phase also demonstrated diminished biofilm viability and epithelial adherence. However, coinfection with influenza virus ameliorated this colonization defectin vivo. Further, viral coinfection ultimately induced a similar magnitude of middle ear infection by both phase variants. These data indicate that despite inherent differences in colonization, the influenza A virus exacerbation of experimental middle ear infection is independent of the pneumococcal phase. These findings provide new insights into the synergistic link between pneumococcus and influenza virus in the context of otitis media.

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