Acute Otitis Media (AOM) is the most common infectious disease among children. During AOM, children typically have diminished hearing and this can lead to temporary delayed speech and language development and possibly permanent hearing loss. This project seeks support to continue our prospective, longitudinal clinical and translational studies of AOM (RO1 DC 08671) with a specific focus on defining the adaptive and innate immune response deficits among otitis prone (OP) children to infections caused by nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). To better understand NTHi and Spn pathogenesis and assist in vaccine development we plan to (1) identify specific adaptive immune deficits in OP children;(2) determine independent contributions of mucosal immunity in OP children;(3) understand the role of innate responses to co-infection of respiratory bacteria and viruses;and (4) define the role of differences in the nasopharyngeal (NP) inflammatory response in shaping the mucosal microenvironment to allow for NTHi/ Spn colonization and then infection. Therefore, we will investigate: 1. The mechanisms causing a diminished capacity to generate adaptive immune responses to NTHi and Spn following NP colonization and AOM in OP versus non-OP (NOP) children. We will define mechanisms causing poor T-cell function with respect to immune maturity and examine the capacity to generate memory T-cells, compare the generation and activity of NTHi/Spn specific B-cells, define key intrinsic differences of antigen-presenting cell function and evaluate mucosal immune responses. 2. The contributions of innate immunity that alters the NP microenvironment to favor NTHi and Spn colonization during concurrent viral infections to aid the pathogenesis of AOM. We will determine the level of NP and middle ear up-regulation of NTHi/Spn epithelial adherence receptors during antecedent respiratory viral infections;define the role of pro-inflammatory cytokine mediators induced by respiratory viral infections in modifying resistance to NTHi/Spn colonization;and characterize expression of toll like receptors (TLR) as mediators of innate and adaptive immune response clearance of NTHi/Spn colonization. During our current funding time interval, we have re-defined the OP child phenotype thereby providing new clarity and direction in the study of these children. Further understanding immune defects in OP children, will point the way to rational design of future candidate vaccines. Second, we will establish the key mediators of "controlled" inflammation in the NP during colonization that promote an effective immune response compared to pathological "uncontrolled" inflammation that allows disease progression. From that knowledge we can seek to modulate or silence those innate immune response pathways that facilitate disease progression while preserving the necessary innate responses that facilitate protective immunogenicity.

Public Health Relevance

This project seeks support to continue our prospective, longitudinal clinical and translational studies of acute otitis media (AOM) (RO1 DC 08671) with a specific focus on defining the adaptive and innate immune response deficits among otitis prone (OP) children to infections caused by nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). We seek to understand the immunity deficits among OP children in the context of overcoming the immune modulating effects of upper respiratory viral infections. To better understand NTHi and Spn pathogenesis and assist in vaccine development we plan to (1) identify specific adaptive immune deficits in OP children;(2) determine independent contributions of mucosal immunity in OP children;(3) understand the role of innate responses to co-infection of respiratory bacteria and viruses;and (4) define the role of differences in the nasopharyngeal (NP) inflammatory response in shaping the mucosal microenvironment to allow for NTHi/Spn colonization and then infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC008671-08
Application #
8610281
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Watson, Bracie
Project Start
2007-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$557,036
Indirect Cost
$143,252
Name
Rochester General Hospital (NY)
Department
Type
DUNS #
043078385
City
Rochester
State
NY
Country
United States
Zip Code
14621
Kaur, Ravinder; Casey, Janet; Pichichero, Michael (2015) Cytokine, chemokine, and Toll-like receptor expression in middle ear fluids of children with acute otitis media. Laryngoscope 125:E39-44
Pichichero, Michael E (2014) Challenges in vaccination of neonates, infants and young children. Vaccine 32:3886-94
Xu, Qingfu; Pichichero, Michael E (2014) Co-colonization by Haemophilus influenzae with Streptococcus pneumoniae enhances pneumococcal-specific antibody response in young children. Vaccine 32:706-11
Verhoeven, David; Xu, Qingfu; Pichichero, Michael E (2014) Differential impact of respiratory syncytial virus and parainfluenza virus on the frequency of acute otitis media is explained by lower adaptive and innate immune responses in otitis-prone children. Clin Infect Dis 59:376-83
Verhoeven, D; Pichichero, M E (2014) Divergent mucosal and systemic responses in children in response to acute otitis media. Clin Exp Immunol 178:94-101
Sharma, Sharad K; Pichichero, Michael E (2013) Cellular immune response in young children accounts for recurrent acute otitis media. Curr Allergy Asthma Rep 13:495-500
Sharma, Sharad K; Roumanes, David; Almudevar, Anthony et al. (2013) CD4+ T-cell responses among adults and young children in response to Streptococcus pneumoniae and Haemophilus influenzae vaccine candidate protein antigens. Vaccine 31:3090-7
Liu, Keyi; Chen, Linlin; Kaur, Ravinder et al. (2013) Transcriptome signature in young children with acute otitis media due to non-typeable Haemophilus influenzae. Int Immunol 25:353-61
Friedel, Victoria; Chang, Arthur; Wills, Jennifer et al. (2013) Impact of respiratory viral infections on *-hemolytic streptococci and otopathogens in the nasopharynx of young children. Pediatr Infect Dis J 32:27-31
Liu, Keyi; Kaur, Ravinder; Almudevar, Anthony et al. (2013) Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by Streptococcus pneumoniae compared to Haemophilus influenzae and Moraxella catarrhalis. Laryngoscope 123:1500-5

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