Contribution of Lipid Mediators in Divergent Outcomes following Acute Bacterial and Viral Lung Infections in the Obese Host [INFECTIOUS DISEASE AND HOST RESPONSE]

Key Points

Obesity reduced susceptibility to pulmonary bacterial infection.

Obesity resulted in a dysregulated lung lipidome and lipid response to infection.

Rapid production of COX-2 products was essential for survival of lung infection.

Visual AbstractFigureFigureAbstract

Obesity is considered an important comorbidity for a range of noninfectious and infectious disease states including those that originate in the lung, yet the mechanisms that contribute to this susceptibility are not well defined. In this study, we used the diet-induced obesity (DIO) mouse model and two models of acute pulmonary infection, Francisella tularensis subspecies tularensis strain SchuS4 and SARS-CoV-2, to uncover the contribution of obesity in bacterial and viral disease. Whereas DIO mice were more resistant to infection with SchuS4, DIO animals were more susceptible to SARS-CoV-2 infection compared with regular weight mice. In both models, neither survival nor morbidity correlated with differences in pathogen load, overall cellularity, or influx of inflammatory cells in target organs of DIO and regular weight animals. Increased susceptibility was also not associated with exacerbated production of cytokines and chemokines in either model. Rather, we observed pathogen-specific dysregulation of the host lipidome that was associated with vulnerability to infection. Inhibition of specific pathways required for generation of lipid mediators reversed resistance to both bacterial and viral infection. Taken together, our data demonstrate disparity among obese individuals for control of lethal bacterial and viral infection and suggest that dysregulation of the host lipidome contributes to increased susceptibility to viral infection in the obese host.

Footnotes

This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant AI001013.

The online version of this article contains supplemental material.

Abbreviations used in this article:

AAarachidonic acidCOX-2cyclooxygenase-2DIOdiet-induced obesityLMlipid mediatorLTleukotrieneLVSlive vaccine strainLXlipoxinMMHmodified Mueller–HintonPC1first principal componentPCAprincipal component analysisPUFApolyunsaturated fatty acidRAGEreceptor for advanced glycation end productsRWregular weightSchuS4Francisella tularensis subspecies tularensis strain SchuS4Received February 25, 2022.Accepted August 2, 2022.

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