Theses Doctoral

Host metabolites in bacterial infection and bioenergetics

Urso, Andreacarola

Staphylococcus aureus is a pulmonary pathogen associated with substantial morbidity and mortality. It is a common complication of influenza and SARS CoV2 infection, chronic obstructive pulmonary disease, cystic fibrosis and is a major cause of ventilator associated pneumonia. The prevalence of this specific organism as a respiratory pathogen has been attributed to its many gene products that thwart innate immunity. However, vaccines targeting virulence determinants have failed to be protective in humans, suggesting that other bacterial or host factors are also critical in pathogenesis.

We postulated that S. aureus that are able to persist in the lung must adapt to substrates that are especially abundant. Here we show that among the many potential carbon sources in the infected airway, S. aureus is directed by carbon catabolite repression (CCR) to utilize proline. By following transcriptomic and metabolomic changes over the initial course of infection by human clinical isolates of S. aureus, we established that CcpA and CcpE upregulate expression of the S. aureus collagenase (scpA) and proline transporter (putP).

In response to infection, airway fibroblasts synthesize collagen, of which proline is a major component. Host-adapted S. aureus is thus poised to ingest and metabolize newly available proline which fuels oxidative metabolism via the TCA cycle, outcompeting strains that have not made this metabolic transition. Thus, clinical settings characterized by airway repair processes and fibrosis provide a milieu that is intrinsically supportive of S. aureus infection.

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More About This Work

Academic Units
Pharmacology and Molecular Signaling
Thesis Advisors
Prince, Alice S.
Degree
Ph.D., Columbia University
Published Here
December 6, 2023