Otitis Media and Bacterial Biofilms

The chronicity and recurrence of many bacterial diseases is largely attributable to the presence of a biofilm. An abundant component of the biofilm is bacterial extracellular DNA, arranged in a lattice and maintained by the DNABII family of bacterial DNA-binding proteins, of which there are only two members: integration hostfactor (IHF) and histone-likeprotein (HU). Both proteins are critical components of the matrix formed by all human pathogens tested to date. Within a biofilm, IHF binds to biofilm DNA via its DNA-binding ‘tip’ regions, and thus the amino terminal (‘tail’) region is exposed. Consequently, the natural immune response is directed against the exposed tail region of IHF, however we’ve shown that antibody directed to this region does not disrupt biofilms. In contrast, antibody that targets the occluded tip regions of IHF induces significant biofilm disruption in vitro and collapses biofilms in the middle ear in an experimental model of otitis media induced by nontypeable Haemophilus influenzae (NTHI). We designed a novel chimeric peptide immunogen that specifically re-routes the immune response to target the protective tip regions of IHF and compared the therapeutic potential for anti-tip chimer peptide antibodies versus anti-native IHF protein. We found that re-direction  of the natural adaptive immune response towards immunoprotective domains of IHF disrupted NTHI biofilms in vitro and in an experimental model of otitis media. Our data support the rational design of a powerful therapeutic approach and that of a DNABII-directed vaccine antigen that would avoid augmentation of any pre-existing natural, but non-protective, immune response.

Bio: Lauren O. Bakaletz, Ph.D. is a Professor of both Pediatrics and Otolaryngology and serves as Director of the Center for Microbial Pathogenesis at The Abigail Wexner Research Institute. She and her team study the molecular mechanisms that underlie polymicrobial infections of the respiratory tract, including otitis media (ear infections), chronic rhinosinusitis and exacerbations of both COPD and cystic fibrosis. Dr. Bakaletz is also Vice President of Basic Sciences, holds the Tillie E. Coleman Endowed Chair in Pediatric Research andwas named an Ohio State University College of Medicine Distinguished Professor in 2013, a lifelong honorific distinction.

The Bakaletz laboratory has been funded by the NIH for over 25 years to pursue the team’s long-standing interest in the design and testing of vaccine candidates for the prevention and/or resolution of otitis media and exacerbations of COPD, including the development of a method to immunize against ear infections by simply placing a ‘band-aid’ on to the skin just behind the ear. In addition, the laboratory has a significant complementary program to study the pathogenesis, prevention and treatment of biofilms, which are towering communities of highly resistant bacteria that are responsible for the majority of chronic and recurrent human and animal diseases. The Bakaletz lab focus on development of novel methods to disrupt and/or prevent biofilm formation is being done in collaboration with the laboratory of Dr. Steven Goodman. As a result of these efforts, Dr. Bakaletz has a vaccine antigen currently in Phase IIB human clinical trials and is the founder of 2 start-up companies.