2023 Theses Doctoral
The itaconate-driven immunometabolic response to S. aureus promotes persistent lung infection
Staphylococcus aureus causes chronic bacterial pneumonias that are resistant to antimicrobial treatment and carry a high burden of morbidity and mortality. S. aureus persists in the lung by assuming adaptive phenotypes like biofilms, which protect the bacteria from antibiotics and host bacterial clearance. It is well established that staphylococcal adaptation to the host is often driven by immune pressure, but the specific factors that drive S. aureus persistence in the setting of chronic lung infection have not been fully elucidated. One of the critical processes that drives immune cell function is metabolism. In addition to fueling the bioenergetic needs of the cell and competing with pathogens for key resources, immune cell metabolism also generates key regulatory metabolites that can either bolster or dampen inflammation in a process known as immunometabolism. The role of these regulatory immune metabolites in staphylococcal pneumonias has not been explored.
This thesis addresses the hypothesis that immune metabolites play an important role in the pathogenesis of S. aureus pneumonias, not only by regulating immune cell function but also by promoting bacterial adaptation to the lung. In Chapter 1, we examine the current understanding of the pathogenesis of staphylococcal lung infections and review the role of immune metabolites in regulating inflammation.
In Chapter 2, we describe the methods we used to test our hypothesis. In Chapter 3, we define the immunometabolic response to S. aureus in the lung, identifying the anti-inflammatory metabolite itaconate as one of the most upregulated metabolites in the infected airway. We determine that itaconate production is triggered by bacterial PAMPs, and is driven by host mitochondrial stress in response to bacterial metabolism. We also discover that neutrophils are the main source of itaconate during staphylococcal pneumonia.
In Chapter 4, we investigate the impact of itaconate on neutrophils, the major immune cell responsible for controlling S. aureus infection. We establish that itaconate impedes bacterial clearance and limits neutrophil bacterial killing. This occurs through two major mechanisms, including inhibition of neutrophil glycolysis, which impairs neutrophil survival during infection, and inhibition of the oxidative burst. We find that neutrophil itaconate production is still beneficial to the host, as it promotes protective, anti-oxidant and anti-cell death pathways in the epithelial and endothelial cells that are critical for respiration.
In Chapter 5, we investigate the impact of itaconate on the metabolic adaptation of S. aureus to the host. We use longitudinal clinical isolates from a patient with chronic staphylococcal pneumonia to define how clonal strains adapt to the inflamed, itaconate-laden lung. The isolates demonstrate that there is selection for strains with reduced bioenergetics but increased biofilm formation. These metabolic changes are recapitulated by exposing a non-adapted S. aureus strain to itaconate, which inhibits staphylococcal bioenergetics via glycolysis, and causes increased utilization of pathways that produce biofilms.
Our data demonstrate that the host immune metabolite itaconate promotes bacterial persistence during staphylococcal pneumonia by impeding bacterial clearance and promoting bacterial biofilm formation. In Chapter 6, we discuss the potential impact of these findings, particularly on the current efforts to develop itaconate as an anti-inflammatory therapeutic, and offer directions for future studies that can further explore how metabolic pathways that normally control inflammation can influence pathogen persistence in the host.
- Tomlinson_columbia_0054D_17619.pdf application/pdf 5.14 MB Download File
More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Prince, Alice S.
- Ph.D., Columbia University
- Published Here
- January 4, 2023