A Perfect Storm: Increased Colonization and Failure of Vaccination Leads to Severe Secondary Bacterial Infection in Influenza Virus-Infected Obese Mice.

Erik A Karlsson,Jason Rosch,Jon Mccullers,Elaine Tuomanen,Nicholas C Van De Velde,Beth Mann,Victoria A Meliopoulos,Peter Vogel,Stacey Schultz-Cherry,Geli Gao,Lee-Ann Van De Velde

doi:10.1128/mbio.00889-17

Abstract

ABSTRACTObesity is a risk factor for developing severe disease following influenza virus infection; however, the comorbidity of obesity and secondary bacterial infection, a serious complication of influenza virus infections, is unknown. To fill this gap in knowledge, lean and obese C57BL/6 mice were infected with a nonlethal dose of influenza virus followed by a nonlethal dose of Streptococcus pneumoniae. Strikingly, not only did significantly enhanced death occur in obese coinfected mice compared to lean controls, but also high mortality was seen irrespective of influenza virus strain, bacterial strain, or timing of coinfection. This result was unexpected, given that most influenza virus strains, especially seasonal human A and B viruses, are nonlethal in this model. Both viral and bacterial titers were increased in the upper respiratory tract and lungs of obese animals as early as days 1 and 2 post-bacterial infection, leading to a significant decrease in lung function. This increased bacterial load correlated with extensive cellular damage and upregulation of platelet-activating factor receptor, a host receptor central to pneumococcal invasion. Importantly, while vaccination of obese mice against either influenza virus or pneumococcus failed to confer protection, antibiotic treatment was able to resolve secondary bacterial infection-associated mortality. Overall, secondary bacterial pneumonia could be a widespread, unaddressed public health problem in an increasingly obese population.

Highlights

IMPORTANCE Worldwide obesity rates have continued to increase
Since both DIO and ob/ob mice showed increased susceptibility to secondary bacterial infection, further studies were conducted with ob/ob mice as a model for morbid obesity, based on their numerous metabolic factors, including hyperglycemian [64]
Treatment of obese mice with ampicillin following secondary bacterial challenge resulted in an 80% increase in survival (20% mortality versus 100%) compared to vehicle-treated controls (Fig. 7e). These results suggest that antibiotic treatment could serve as an adequate countermeasure to bacterial infections in the influenza virusinfected obese host, and further work is warranted on these protective measures

Summary

Introduction

IMPORTANCE Worldwide obesity rates have continued to increase. Obesity is associated with increased severity of influenza virus infection; very little is known about respiratory coinfections in this expanding, high-risk population. Influenza virus infection alone in the obese host has been associated with all of these risk factors, including increased airway damage, altered inflammation, and decreased immune function [1, 13] These factors raise the question of synergistic destruction between secondary bacterial coinfection in the setting of obesity; the mechanism of copathogenesis of obesity and secondary bacterial coinfection is unknown. Vaccinating obese mice against either influenza virus or pneumococcus failed to protect against the increased morbidity associated with coinfection; antibiotic treatment succeeded in protecting obese mice from secondary bacteria-associated mortality Overall, these results indicate that secondary bacterial pneumonia is likely to be a problem in an increasingly obese population

Methods

Results

Conclusion