Continuous Microevolution Accelerates Disease Progression during Sequential Episodes of Infection
Alistair Harrison,
Rachael L. Hardison,
Audra R. Fullen,
Rachel M. Wallace,
David M. Gordon,
Peter White,
Ryan N. Jennings,
Sheryl S. Justice,
Kevin M. Mason
Affiliations
Alistair Harrison
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Rachael L. Hardison
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Audra R. Fullen
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
Rachel M. Wallace
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
David M. Gordon
The Steve and Cindy Rasmussen Institute of Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43215, USA
Peter White
The Steve and Cindy Rasmussen Institute of Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43215, USA
Ryan N. Jennings
College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
Sheryl S. Justice
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Infectious Disease Institute, The Ohio State University, Columbus, OH 43205, USA; Corresponding author
Kevin M. Mason
Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; Infectious Disease Institute, The Ohio State University, Columbus, OH 43205, USA; Corresponding author
Summary: Bacteria adapt to dynamic changes in the host during chronic and recurrent infections. Bacterial microevolution is one type of adaptation that imparts a selective advantage. We hypothesize that recurrent episodes of disease promote microevolution through genetic mutations that modulate disease severity. We use a pre-clinical model of otitis media (OM) to determine the potential role for microevolution of nontypeable Haemophilus influenzae (NTHI) during sequential episodes of disease. Whole genome sequencing reveals microevolution of hemoglobin binding and lipooligosaccharide (LOS) biosynthesis genes, suggesting that adaptation of these systems is critical for infection. These OM-adapted strains promote increased biofilm formation, inflammation, stromal fibrosis, and an increased propensity to form intracellular bacterial communities (IBCs). Remarkably, IBCs remain for at least one month following clinical resolution of infection, suggesting an intracellular reservoir as a nidus for recurrent OM. Additional approaches for therapeutic design tailored to combat this burdensome disease will arise from these studies. : Harrison et al. develop a sequential model of otitis media (OM) to investigate microevolution through genetic mutations that modulate disease severity. OM-adapted strains promote increased biofilm, inflammation, stromal fibrosis, and intracellular bacterial community (IBC) development. IBCs remain one month following clinical resolution of infection, suggesting a nidus for recurrent OM. Keywords: Haemophilus, microevolution, otitis media, persistence, intracellular bacterial communities, lipooligosaccharide, hemoglobin, recurrence
