Targeting a Bacterial Switch to Treat Chronic Ear Infections

November 29, 2018
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An understanding of how bacteria adapt to microenvironments in the body could help clear persistent ear infections.

Middle ear infections can persist and re-occur in children, even with repeated rounds of antibiotics. Researchers at Nationwide Children’s Hospital are working to understand how the bacteria responsible for these infections are able to adapt and evade both antibiotic treatments and the immune system, with the ultimate goal of designing more effective strategies for treatment and prevention.

One of the factors contributing to the chronic and recurrent nature of ear infections is the formation of a biofilm in the middle ear. A biofilm is a community of bacteria that have formed a protective matrix, making the bacteria more resistant to antimicrobial treatments and the immune system. Many human pathogenic bacteria form biofilms, especially throughout the gut and airways.

The bacterium Nontypeable Haemophilus influenzae (NTHI), the predominant cause of chronic and recurrent middle ear infections, has another unique mechanism that allows it to adapt to different environments within the human body. NTHI typically resides asymptomatically in the nasal cavity. However, when a child gets a cold or has some other immune deficiency, these bacteria can move up into the ear and sinuses and cause infection. Like some other human pathogens, these bacteria have evolved a mechanism of rapid adaptation, called the phase variable regulon or phasevarion, which facilitates a coordinated regulation of many bacterial genes. The phasevarion of NTHI allows the bacteria to adapt and persist within other environments of the airway, such as the middle ear, that may otherwise be hostile to these bacteria.

“You have a single bacterium that can behave one of two ways,” says Kenneth Brockman, a post-doctoral researcher in the Center for Microbial Pathogenesis at Nationwide Children’s and co-author of a new paper on phasevarion regulation in NTHI. “I think of it as a Dr. Jekyll and Mr. Hyde-type situation, where the bacteria can switch between two states depending on the conditions: one that may not be bad and another that can cause disease.”

In the new study, Dr. Brockman and his colleagues looked at how the switch between these two states by the phasevarion affects biofilms throughout the airway. They analyzed biofilm formation on glass in the laboratory under different temperature and pH combinations that are relevant to disease.

Dr. Brockman and his colleagues discovered that the biofilms formed varied with the different conditions. The impact of phasevarion regulation was greatest in the 37 degrees Celsius and alkaline pH condition, which mimics the environment of the middle ear during chronic disease.

“The fact that the phasevarion had significant implications on how the biofilms are formed under conditions within the middle ear, but not conditions in other parts of the airway such as the nasopharynx, suggests that this mechanism allows these bacteria to adapt to changing environmental conditions as they move throughout the airway,” says Dr. Brockman.

The findings could aid in the design of improved strategies against NTHI infections, as well as diseases caused by other pathogens that use a phasevarion.

Dr. Brockman says an increased understanding of the role of the phasevarion in biofilm formation will lead to the development of new combinatorial strategies that target the entire NTHI population, not only preventing but also treating chronic ear infections.

“To develop treatments or preventative measures, we need to identify targets on the bacteria or specific behaviors of the bacteria to exploit so we can treat these infections,” says Dr. Brockman.

“Ideally, we would like to target both populations of NTHI – getting rid of Mr. Hyde and Dr. Jekyll to really clear both populations of bacteria.”



Brockman KL, Azzari PN, Branstool MT, Atack JM, Schulz BL, Jen FE-C, Jennings MP, Bakaletz LO. Epigenetic regulation alters biofilm architecture and composition in multiple clinical isolates of Nontypeable Haemophilus influenzaemBio. 2018;9:e01682-18.

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