Project Summary / Abstract
We request NIH support to investigate how sensory hearing loss (SHL) is caused by chronic suppurative otitis
media (CSOM) or severe chronic middle ear infections. CSOM, a neglected tropical disease that afflicts 330
million people worldwide, is the most common cause of permanent hearing loss among children in the
developing world. It is characterized by a chronically discharging infected middle ear, and there is currently no
effective medical therapy or cure. The bacterium, Pseudomonas aeruginosa (PA), is the leading culprit. PA
colonizes the middle ear via a hole in the tympanic membrane and establishes itself into a biofilm community,
complicating attempts to treat and fully eradicate infection. Over the course of the disease, the infection waxes
and wanes as the population of bacteria within the biofilm responds, in part, to immune attack or topical
antibiotics. This waxing and waning of bacterial infection leads to permanent sensory hearing loss via an
unknown mechanism. Our lab has recently created and validated a novel PA CSOM animal model that mimics
the human condition. Specifically, we create the infection by inoculating PA in the right state (phenotype) and
dose, which results in an infection that persists beyond six months, waxes and wanes upon topical
fluoroquinolone therapy, and leads to hair cell death, over time, like in the human disease. Previous
investigations by others relied on acute infection models based on non-PA bacteria. In contrast, our unique
model of PA CSOM now allows us to observe development of the infection in the inner ear and identify agents
and/or processes that may be causing the resulting sensory hearing loss. Our studies would help determine
whether permanent hearing loss is preventable in CSOM and, if so, guide strategies for therapeutic intervention.
Our Aims encompass: (1) determining the timing and nature of structural changes occurring within the cochlea
and assessing the macrophage distribution as these changes occur, (2) investigating potential direct hair cell
(HC) toxins and macrophage inducers through CSOM perilymph sampling, and (3) evaluating the contributions
of resident and migrating macrophages towards hair cell loss in CSOM by combining our CSOM mouse model
with the CD68-GFP transgenic reporter mouse and, separately, with a triple knockout mouse strain with
macrophages unable to produce reactive oxygen species (ROS) while also evaluating whether NLRP3
inflammasome function is necessary for HC loss in the cochlea.
Altogether these aims are a completely new approach to sensory hearing loss caused by CSOM. If successful,
these studies will support future investigations into the mechanisms in the pathophysiology of CSOM and lead
to novel treatments for PA and potential strategies to prevent sensory hearing loss in CSOM.
