[R01] The role of pyruvate acquisition in the survival of Staphylococcus aureus within an intracellular environment
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2031-05-31
Importo max: 586.920 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Recent studies have demonstrated the dual roles of the Staphylococcus aureus lrgAB and cidABC
operons. Originally characterized as effectors of bacterial programmed cell death (PCD), they are now
known to also mediate the transport of products of carbohydrate metabolism. Preliminary results from our
group revealed that the S. aureus lrgAB operon is required for the uptake of pyruvate under microaerobic
conditions, is important for survival within macrophages (MΦs), and for colonization in a mouse model of
prosthetic joint infection (PJI). Pyruvate is a key metabolite generated in the cytoplasm of eukaryotic cells
through the action of the glycolytic pathway. Once generated, this metabolite is then transported via
Mitochondrial Pyruvate Carrier (MPC) proteins into the mitochondria where it is catabolized in the TCA
cycle and completely oxidized through the respiratory chain. Recent results have revealed additional S.
aureus genes (lctP, lldP, and B7H15_13955) involved in pyruvate import and suggest the presence of a
complex system required for the uptake of this important metabolite from the environment. Based on our
preliminary results, we hypothesize that upon entry into MΦs, S. aureus competes with mitochondria
for limited pyruvate pools using specific pyruvate transporters. This hypothesis will be tested by 1)
characterizing the regulation and physiological roles of the lrgAB-, lctP-, lldP-, and B7H15_13955-encoded
transporters during S. aureus growth, 2) examining the effect of pyruvate transport on survival and growth
within macrophages, and 3) establishing the role of this system during PJI and the impact of S. aureus
pyruvate import on the metabolism and activity of macrophages during an infection. The data generated
by these studies will lead to an improved understanding of the functions of the LrgAB, LctP, LldP, and
B7H15_13955 proteins and their role in pyruvate assimilation. In addition, these results will reveal the
impact of these proteins on the physiology of S. aureus growth and determine the biological role of this
system during intracellular survival. Overall, the discoveries generated during the course of this project will
provide a new perspective on staphylococcal pathogenesis that will aid in the development of more
effective therapeutic strategies to treat diseases caused by this pathogen.
Istituzione: UNIVERSITY OF NEBRASKA MEDICAL CENTER
PI: KENNETH W. BAYLES
Progetto: 1R01AI192925-01A1
Settori: National Institute of Allergy and Infectious Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.