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One such niche inhabited by\n                      <jats:italic toggle=\"yes\">Listeria monocytogenes<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">L. monocytogenes<\/jats:italic>\n                      ) is the host cell cytosol, a compartment characterized by significant barriers to entry, metabolic limitation, and immune surveillance. Previously, we identified\n                      <jats:italic toggle=\"yes\">L. monocytogenes<\/jats:italic>\n                      transposon mutants defective for intracellular survival due to disruptions in key metabolic pathways, including cell wall biosynthesis, menaquinone production, and pyruvate metabolism. Here, we demonstrate that mutations in the pyruvate dehydrogenase (PDH) complex exhibit pronounced survival defects during infection, despite retaining robust growth and survival in nutrient-rich media. Metabolomic profiling of the PDH E2 subunit mutant revealed an altered respiro-fermentative metabolism with lower levels of both upper glycolytic intermediates and tricarboxylic acid cycle intermediates coupled with elevated levels of pyruvate and lactate. Additionally, we found that PDH mutants are unable to efficiently utilize phosphotransferase system (PTS)-dependent carbon sources, but their growth is indistinguishable from that of the wild type on non-PTS carbon sources such as hexose phosphates. A suppressor screen identified five suppressor mutants with restored ability to grow on the PTS substrate fructose, and each contained an independent mutation in the redox-sensing regulator\n                      <jats:italic toggle=\"yes\">rex<\/jats:italic>\n                      . Loss of Rex function in PDH mutants partially restored intracellular growth, but not virulence\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Together, these findings demonstrate that PDH is required for the import and metabolism of PTS-dependent carbon sources in the host cytosol and suggest that PDH-dependent redox balance and respiro-fermentative metabolism ultimately contribute to intracellular fitness and virulence.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00505-25","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T22:45:55Z","timestamp":1780094755000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Understanding the role of pyruvate dehydrogenase in\n                    <i>Listeria monocytogenes<\/i>\n                    virulence"],"prefix":"10.1128","volume":"94","author":[{"given":"Matthew J.","family":"Freeman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y2jtd41","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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