{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:06:44Z","timestamp":1777612004742,"version":"3.51.4"},"reference-count":67,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R21AI166581"],"award-info":[{"award-number":["R21AI166581"]}]},{"name":"HHS | National Institutes of Health","award":["T32AI138954"],"award-info":[{"award-number":["T32AI138954"]}]},{"name":"HHS | National Institutes of Health","award":["S10OD028540"],"award-info":[{"award-number":["S10OD028540"]}]},{"name":"University of Pittsburgh Department of Medicine","award":["KARAT Catalytic Grant"],"award-info":[{"award-number":["KARAT Catalytic Grant"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Persistent infection by\n            <jats:italic>Staphylococcus aureus<\/jats:italic>\n            has been linked to the bacterial stringent response (SR), a conserved stress response pathway regulated by the Rel protein. Rel synthesizes (p)ppGpp \u201calarmones\u201d in response to amino acid starvation, which enables adaptation to stress by modulating bacterial growth and virulence. We previously identified five novel protein-altering mutations in\n            <jats:italic>rel<\/jats:italic>\n            that arose in patients with persistent methicillin-resistant\n            <jats:italic>S. aureus<\/jats:italic>\n            bacteremia. The mutations mapped to both the enzymatic and regulatory protein domains of Rel. Here, we set out to characterize the phenotype of these mutations to understand how they may have been selected\n            <jats:italic>in vivo<\/jats:italic>\n            . After introducing each mutation into\n            <jats:italic>S. aureus<\/jats:italic>\n            strain JE2, we analyzed growth, fitness, and antibiotic profiles. Despite being located in different protein domains, we found that all of the mutations converged on the same phenotype. Each shortened the time of lag phase growth and imparted a fitness advantage in nutritionally depleted conditions. Through quantification of intracellular (p)ppGpp, we link this phenotype to increased SR activation, specifically during the stationary phase of growth. In contrast to two previously identified clinical\n            <jats:italic>rel<\/jats:italic>\n            mutations, we find that our\n            <jats:italic>rel<\/jats:italic>\n            mutations do not cause antibiotic tolerance. Instead, our findings suggest that\n            <jats:italic>in vivo<\/jats:italic>\n            selection was due to an augmented SR that primes cells for growth in nutrient-poor conditions, which may be a strategy for evading host-imposed nutritional immunity.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>Importance<\/jats:title>\n            <jats:p>\n              Host and pathogen compete for available nutrition during infection. For bacteria, the stringent response (SR) regulator Rel responds to amino acid deprivation by signaling the cell to modulate its growth rate, metabolism, and virulence. In this report, we characterize five\n              <jats:italic>rel<\/jats:italic>\n              mutations that arose during cases of persistent methicillin-resistant\n              <jats:italic>Staphylococcus aureus<\/jats:italic>\n              bacteremia. We find that all of the mutations augmented SR signaling specifically under nutrient-poor conditions, enabling the cell to more readily grow and survive. Our findings reveal a strategy used by bacterial pathogens to evade the nutritional immunity imposed by host tissues during infection.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00249-23","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T13:01:38Z","timestamp":1695733298000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Clinical\n            <i>rel<\/i>\n            mutations in\n            <i>Staphylococcus aureus<\/i>\n            prime pathogen expansion under nutrient stress"],"prefix":"10.1128","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-3537","authenticated-orcid":false,"given":"Edwin","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marla G.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert E.","family":"Bilodeau","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"Raymond E.","family":"West","sequence":"additional","affiliation":[{"name":"Small Molecule Biomarker Core, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick J.","family":"Oberly","sequence":"additional","affiliation":[{"name":"Small Molecule Biomarker Core, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas D.","family":"Nolin","sequence":"additional","affiliation":[{"name":"Small Molecule Biomarker Core, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8327-4135","authenticated-orcid":false,"given":"Matthew J.","family":"Culyba","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, USA"},{"name":"Center for Evolutionary Biology and Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania, 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