There have been tremendous recent advances in our understanding of the pathogenesis of otitis media (OM) due to nontypeable Haemophilus influenzae (NTHI). Significantly, we've come to appreciate the role that biofilms play in the chronicity and recurrence of NTHI-induced OM. Bacteria dwelling within a biofilm present a formidable obstacle to effectors of immunity and antibiotic therapies. Thereby, in order to design novel and effective strategies to better treat and/or prevent OM, it is necessary to understand both the biology of biofilms, including their unique biochemical and proteomic composition, as well as how one might undermine these structures to mediate a therapeutic or preventative 'cure'. To do so, herein we propose a series of three highly integrated specific aims. Through the successful conduct of the experimentation proposed in these aims, we will expand upon highly promising preliminary data which show that targeting a bacterial protein that stabilizes extracellular DNA (eDNA) present within a biofilm structure is highly effective for reducing or eradicating that structure both in vitro and in vivo. Moreover, we will begin to define the molecular mechanisms that underlie this effective strategy, attempt to unravel the immune correlates of the observed protection, expand upon studies that will explore the observed synergy between antibodies directed against IHF (a DNA binding protein) and other enzymes, antibodies and/or antibiotics, then apply our advanced understanding to the design and testing of novel vaccine candidates and therapeutics for the prevention or treatment of OM using a chinchilla model of this important polymicrobial disease, respectively. The chinchilla model of OM represents a robust, reproducible and extensively studied animal model of this highly prevalent pediatric disease in which to establish these essential proof-of-principle findings. Moreover, whereas our primary target for disease intervention is OM, because NTHI causes many biofilm-associated diseases of the human respiratory tract, the studies proposed here will also likely provide better approaches to use for disease in other parts of the airway such as the sinuses (chronic rhinosinusitis), the tonsils and adenoids (tonsillitis, adenoiditis), the bronchus (chronic cough and bronchitis) and the lung (COPD, early stage CF, community acquired pneumonia). Our goals are thus fully in keeping with both Healthy People 2010 (28: Vision and Hearing, Section 28-12), and the NIDCD strategic plan FY 2009-2011, wherein a priority research area is Molecular and Non-genetic Basis of Normal and Disordered Communication Processes. Specifically, we will continue our long-standing efforts to "explore the pathogenesis, treatment and prevention of viral and bacterial infections that contribute to communication disorders" (i.e. hearing loss due to OM), a goal of Strategic Plan Priority Area I.
There were 24.5 million physician's office visits made for middle ear infections [or otitis media (OM)] in 1990 in the United States alone. Moreover, worldwide it is reported that between 65 and 330 million children suffer from chronic secretory OM, 60% of which have an associated hearing loss from this disease state that is characterized by chronically draining ears that can extend over a period of years. The most cost-effective way to manage this highly prevalent pediatric disease, and have a transformational effect on the health of children globally, is through the development of novel methods to better treat OM, as well as the design of innovative vaccines to prevent OM, both of which are the overarching goals of our collaborative research program.
|Brockson, M Elizabeth; Novotny, Laura A; Mokrzan, Elaine M et al. (2014) Evaluation of the kinetics and mechanism of action of anti-integration host factor-mediated disruption of bacterial biofilms. Mol Microbiol 93:1246-58|
|Novotny, Laura A; Amer, Amal O; Brockson, M Elizabeth et al. (2013) Structural stability of Burkholderia cenocepacia biofilms is reliant on eDNA structure and presence of a bacterial nucleic acid binding protein. PLoS One 8:e67629|
|Gustave, Jodi E; Jurcisek, Joseph A; McCoy, Karen S et al. (2013) Targeting bacterial integration host factor to disrupt biofilms associated with cystic fibrosis. J Cyst Fibros 12:384-9|
|Brandstetter, Kathleyn A; Jurcisek, Joseph A; Goodman, Steven D et al. (2013) Antibodies directed against integration host factor mediate biofilm clearance from Nasopore. Laryngoscope 123:2626-32|