Abstract Advances in our understanding of otitis media is slowed by limitations of experimental systems that, for example, inject large inocula of human pathogens into the middle ears of rodents. Such approaches bypass the progression from natural colonization to disease, and the pathogens fail to persist in the middle ears as chronic infections, the period when complications of the disease usually begin to set in. We recently observed that the gram-negative bacteria Bordetella bronchiseptica and Bordetella pseudohinzii are very efficient colonizers of the middle ears of mice. Despite being phylogenetically related, B. bronchiseptica efficiently induces acute inflammation but fails to establish a chronic infection. B. pseudohinzii also induces an early acute inflammatory response but persists indefinitely as a chronic infection in the middle ears, inducing hearing loss and pathology mimicking chronic otitis media in humans. Here, we will use these two contrasting pathogen models of otitis media to uncover the virulence factors of oto-pathogens that lead to chronic infection and uncover host immune mechanisms that determine acute versus chronic infections. We will make genome comparisons to highlight their genetic differences and then focus on the stage specific transcriptional profiles of these genes as B. pseudohinzii and B. bronchiseptica progress through the early, acute and chronic stages of middle ear infection in mice. From this list of uniquely expressed genes, we will prioritize and select putative genes implicated in the different stages of infection. We will then delete these to assess the roles of each in pathogenesis and persistence. We also propose to make preliminary investigations of the adaptive immune system and to establish the difference in the host response when confronted with acute and chronic middle ear pathogens.