Otitis media (OM) is one of the most common of childhood diseases and a major public health problem. The disease can lead to middle ear and inner ear pathology and hearing loss. There are fundamental gaps in our understanding of how bacterial pathogens in OM cause the inflammatory response in the middle ear, the mechanism of middle and inner ear interaction, inner ear pathology, and hearing loss. This prompted us to develop a cogent investigation of the molecular processes underlying migration of infectious agents from the middle to the inner ear and the effects of such migration on the ear pathology. Widespread use of antibiotics has resulted in an increase of antibiotic-resistant Streptococcus pneumoniae and an increased potential for chronic OM development and its complications. Although polysaccharide vaccines have been developed, there are more than 90 distinct serotypes for S. pneumoniae, and antibodies against one serotype generally do not protect against another. The current 7-valent pneumococcal conjugate vaccine PCV7 is 100% efficacious against invasive pneumococcal disease of vaccine serotypes in children <2-years old, but only 34% against acute OM. A protein-based vaccine may overcome this limitation by including antigens conserved among different pneumococcal serotypes. Our long-term goal is to develop novel approaches for prevention and treatment of OM and its complications. In this application, we propose a new strategy for prevention of OM and its complications that relies on a combination of PspA and other pneumococcal proteins. We will utilize different mutant bacterial strains and immunization of animals against these proteins. Our objective is to understand the role of bacterial virulence factors in bacterial invasion, colonization, and pathogenesis in the middle and inner ears for therapeutic targeting and to develop a vaccine composition that optimally neutralizes the most critical protein virulence factors. Our central hypothesis is that PspA and other bacterial proteins affect the pathology of the middle and inner ears. Bacterial components and inflammatory mediators produced in the middle ear pass through the round window membrane into the inner ear, damage cochlear structures, resulting in hearing loss. Our rationale is that knowing how bacterial components affect the pathology of the middle and inner ears will make it possible to design new approaches for the prevention and treatment of OM. These considerations have led to the formulation of our Specific Aims: 1) To identify the role of pneumococcal PspA protein and its combination with other potential pneumococcal vaccine proteins on the middle and inner ear and strategies for prevention of OM;2) To identify mechanisms of inner ear damage and auditory dysfunction caused by live S. pneumoniae. The results gained from these studies will provide new insights into the roles of S. pneumoniae virulence factors in the development of OM and inner ear complications. To achieve our goal we have assembled a group of PIs who have collaborated in recent years, and who are uniquely qualified to address this challenge with their combined expertise.

Public Health Relevance

These studies will use innovative approaches to determine the effects of important pneumococcal virulence proteins and their combination on the middle and inner ears. Understanding the role of bacterial virulence factors and host defense using mutant strains and immunization experiments may have an important positive impact to facilitate the development of new strategies for prevention and treatment of otitis media and its complications, especially significant in the era of multi-drug resistant bacteria, by selection of bacterial proteins for future vaccine design against pneumococcal otitis media, such as protein- based or conjugate polysaccharide vaccine with pneumococcal proteins as carriers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006452-08
Application #
8664361
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Watson, Bracie
Project Start
2003-12-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$295,838
Indirect Cost
$77,220
Name
University of Minnesota Twin Cities
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Vianna, Melissa; Adams, Meredith; Schachern, Patricia et al. (2014) Differences in the diameter of facial nerve and facial canal in bell's palsy--a 3-dimensional temporal bone study. Otol Neurotol 35:514-8
Schachern, Patricia A; Tsuprun, Vladimir; Ferrieri, Patricia et al. (2014) Pneumococcal PspA and PspC proteins: potential vaccine candidates for experimental otitis media. Int J Pediatr Otorhinolaryngol 78:1517-21
Yildirim-Baylan, Muzeyyen; Schachern, Patricia; Tsuprun, Vladimir et al. (2014) The pathology of silent otitis media: a predecessor to tympanogenic meningitis in infants. Int J Pediatr Otorhinolaryngol 78:451-4
Croney, Christina M; Nahm, Moon H; Juhn, Steven K et al. (2013) Invasive and noninvasive Streptococcus pneumoniae capsule and surface protein diversity following the use of a conjugate vaccine. Clin Vaccine Immunol 20:1711-8
Schachern, Patricia A; Tsuprun, Vladimir; Goetz, Sarah et al. (2013) Viability and virulence of pneumolysin, pneumococcal surface protein A, and pneumolysin/pneumococcal surface protein A mutants in the ear. JAMA Otolaryngol Head Neck Surg 139:937-43
Yoda, Shigetoshi; Cureoglu, Sebahattin; Paparella, Michael M (2011) Pulmonary carcinoma metastasis to the internal auditory canal. Otol Neurotol 32:e48-9
Yoda, Shigetoshi; Cureoglu, Sebahattin; Shimizu, Shigetaka et al. (2011) Round window membrane in Meniere's disease: a human temporal bone study. Otol Neurotol 32:147-51
Joglekar, Shruti; Morita, Norimasa; Cureoglu, Sebahattin et al. (2010) Cochlear pathology in human temporal bones with otitis media. Acta Otolaryngol 130:472-6
Schachern, Patricia A; Tsuprun, Vladimir; Cureoglu, Sebahatin et al. (2010) Effect of apolactoferrin on experimental pneumococcal otitis media. Arch Otolaryngol Head Neck Surg 136:1127-31
Schachern, Patricia A; Tsuprun, Vladimir; Wang, Beinan et al. (2009) Effect of lipooligosaccharide mutations of Haemophilus influenzae on the middle and inner ears. Int J Pediatr Otorhinolaryngol 73:1757-60

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