This project aims to define how polymicrobial infection impacts the development, severity, and treatment of bacterial otitis media. Haemophilus influenzae (Hi) is the leading bacterial species associated with otitis media, and our data show that coinfection with multiple strains of Hi is common. We hypothesize that strains of Hi undergo intrastrain and interstrain quorum signaling and horizontal gene transfer within biofilm communities which impacts strain diversity and horizontal dissemination of virulence determinants. In order to address these hypotheses we will complete the following Specific Aims:
Specific Aim 1. To understand relationships between Hi strains with differing production and/or sensing of quorum signal Specific Aim 2. To ask how different inters train relationships affect bacterial persistence and disease severity in the chinchilla infection model Specific Aim 3. To define emergence and dissemination of virulence determinants among Hi strains within the same biofilm community. Otitis media is among the most common pediatric infectious diseases, affecting the majority of children and accounting for billions of dollars in ttal health-care costs per year. It is clear that a significant proportion of these infections are cause by Hi, for which there is no currently licensed vaccine. Unfortunately, our ability to treat these infections is increasingly limited by the continued emergence of antibiotic-resistant bacterial strains. The results of these studies will provide significant insight into how different Hi strain act competitively and/or cooperatively during infection. Moreover, we will gain significant new information regarding how new genotypes emerge and are disseminated within a biofilm community. These findings will be crucial steps in gaining the deep understanding of basic mechanisms for persistence and virulence that will be necessary for tailoring new strategies for diagnosis, prevention, and/or therapy of otitis media infections.

Public Health Relevance

Otitis media is a major common and costly pediatric illness worldwide, accounting for billions of dollars per year in total economic impact. Otitis media infections are the leading reason for pediatric office visits, new antibiotic prescriptions, and surgical instillation of tympanic drain tubes to relieve chronic and recurrent otitis media is the most commonly performed surgical procedure in the U.S. and it is clear that Haemophilus influenzae is a major cause of these infections. It is thus of great importance to improve our knowledge of H. influenzae biology and pathogenesis. In particular, the completion of the work proposed in this application will shed new light on mechanisms for emergence and dissemination of new genotypes, which is a crucial issue as antibiotic resistance becomes more widespread.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DC010051-06
Application #
8580507
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Watson, Bracie
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Murrah, Kyle A; Pang, Bing; Richardson, Stephen et al. (2015) Nonencapsulated Streptococcus pneumoniae causes otitis media during single-species infection and during polymicrobial infection with nontypeable Haemophilus influenzae. Pathog Dis 73:
Murrah, Kyle A; Turner, Roberta L; Pang, Bing et al. (2015) Replication of type 5 adenovirus promotes middle ear infection by Streptococcus pneumoniae in the chinchilla model of otitis media. Pathog Dis 73:1-8
Holder, Robert C; Kirse, Daniel J; Evans, Adele K et al. (2015) Otopathogens Detected in Middle Ear Fluid Obtained during Tympanostomy Tube Insertion: Contrasting Purulent and Non-Purulent Effusions. PLoS One 10:e0128606
Wren, John T; Blevins, Lance K; Pang, Bing et al. (2014) Influenza A virus alters pneumococcal nasal colonization and middle ear infection independently of phase variation. Infect Immun 82:4802-12
Blevins, Lance K; Wren, John T; Holbrook, Beth C et al. (2014) Coinfection with Streptococcus pneumoniae negatively modulates the size and composition of the ongoing influenza-specific CD8⁺ T cell response. J Immunol 193:5076-87
Perez, Antonia C; Pang, Bing; King, Lauren B et al. (2014) Residence of Streptococcus pneumoniae and Moraxella catarrhalis within polymicrobial biofilm promotes antibiotic resistance and bacterial persistence in vivo. Pathog Dis 70:280-8
Swords, W Edward (2012) Nontypeable Haemophilus influenzae biofilms: role in chronic airway infections. Front Cell Infect Microbiol 2:97
Pang, Bing; Hong, Wenzhou; Kock, Nancy D et al. (2012) Dps promotes survival of nontypeable Haemophilus influenzae in biofilm communities in vitro and resistance to clearance in vivo. Front Cell Infect Microbiol 2:58
Holder, Robert C; Kirse, Daniel J; Evans, Adele K et al. (2012) One third of middle ear effusions from children undergoing tympanostomy tube placement had multiple bacterial pathogens. BMC Pediatr 12:87
Swords, W Edward (2012) Quorum signaling and sensing by nontypeable Haemophilus influenzae. Front Cell Infect Microbiol 2:100

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