Date of Award

12-14-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Jian-Dong Li

Abstract

Otitis media (OM) and chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), are leading causes of antibiotic prescriptions across the globe and of serious economic concern regarding rising healthcare costs in the U.S. These conditions affect billions of people globally and cost billions in healthcare dollars annually as well. An in depth understanding of these disease processes will lead to more effective therapies and reduced healthcare costs overall. Nontypeable Haemophilus influenzae (NTHi) is a major pathogen associated with OM and COPD, which are both characterized by inflammation and mucous production at the site of infection. Mucous is part of the innate immune defenses against infection, and like other innate defenses, mucous production must be tightly regulated across all mucosal tissues to avoid deleterious effects and spread of infection. In this dissertation, we show that mice deficient in RIP-2 have reduced NTHi burden in the middle ear after infection through the tympanic membrane and mice deficient in NLRP3 have prolonged infection with NTHi. Our data suggest a role for RIP-2 in establishing NTHi infection within the middle ear. We also investigate the role of RIP-2 in NTHi infection in vitro and in vivo. We show that RIP-2 is a negative regulator of MUC5AC, a key mucin produced in the upper respiratory tract, whereas c-Jun N-terminal kinase (JNK) is a positive regulator of MUC5AC. Our studies provide evidence that RIP-2 plays a novel role in controlling mucous production in upper respiratory tract. Together, these data suggest that RIP-2 may be a potential therapeutic target to control mucous production and NTHi infection in mucosal tissues.

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