{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T22:15:32Z","timestamp":1779228932505,"version":"3.51.4"},"reference-count":55,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R35GM147519"],"award-info":[{"award-number":["R35GM147519"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI137070"],"award-info":[{"award-number":["R01AI137070"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2024,12,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              C-di-AMP homeostasis is critical for bacterial stress response, cell wall integrity, and virulence. Except for osmotic stress response, the molecular mechanisms underlying other processes are not well defined. A\n              <jats:italic>Listeria monocytogenes<\/jats:italic>\n              mutant lacking both c-di-AMP phosphodiesterases, denoted as the \u0394PDE mutant, is significantly attenuated in the mouse model of systemic infection. We utilized the \u0394PDE mutant to define the molecular functions of c-di-AMP. RNAseq revealed that the \u0394PDE mutant is significantly impaired for the expression of virulence genes regulated by the master transcription factor PrfA, which is activated by reduced glutathione (GSH) during infection. Subsequent quantitative gene expression analyses revealed that the \u0394PDE strain is defective for PrfA-regulated gene expression both at the basal level and upon activation by GSH. We further found the \u0394PDE strain to be significantly depleted for cytoplasmic GSH and impaired for GSH uptake. The \u0394PDE strain was also deficient in GSH under conditions that activate GSH synthesis by the synthase GshF and upon constitutive expression of\n              <jats:italic>gshF<\/jats:italic>\n              , suggesting that c-di-AMP accumulation inhibits GSH synthesis activity or promotes GSH catabolism. A constitutively active PrfA* variant restored virulence gene expression in \u0394PDE in broth cultures supplemented with GSH but did not rescue virulence defect\n              <jats:italic>in vivo<\/jats:italic>\n              . Therefore, virulence attenuation at high c-di-AMP is likely associated with defects outside of the PrfA regulon. For instance, the \u0394PDE strain was sensitive to oxidative stress, a phenotype exacerbated in the absence of GshF. Our data reveal GSH metabolism as another pathway that is regulated by c-di-AMP.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                C-di-AMP regulates both bacterial pathogenesis and interactions with the host. Although c-di-AMP is essential in many bacteria, its accumulation also attenuates the virulence of many bacterial pathogens. Therefore, disrupting c-di-AMP homeostasis is a promising antibacterial treatment strategy and has inspired several studies that screened for chemical inhibitors of c-di-AMP phosphodiesterases. However, the molecular functions of c-di-AMP are still not fully defined, and the underlying mechanisms for attenuated virulence at high c-di-AMP levels are unclear. Our analyses in\n                <jats:italic>Listeria monocytogenes<\/jats:italic>\n                indicate that virulence-related defects are likely outside of the virulence gene regulon. We found c-di-AMP accumulation to impair\n                <jats:italic>L. monocytogenes<\/jats:italic>\n                virulence gene expression and disrupt GSH metabolism. Further studies are necessary to establish the relative contributions of these regulations to virulence and host adaptation.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/iai.00440-24","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T14:00:28Z","timestamp":1732024828000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["C-di-AMP accumulation disrupts glutathione metabolism in\n            <i>Listeria monocytogenes<\/i>"],"prefix":"10.1128","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-0556","authenticated-orcid":true,"given":"Cheta","family":"Siletti","sequence":"first","affiliation":[{"name":"Microbiology Doctoral Training Program, University of Wisconsin\u2013Madison","place":["Madison, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin\u2013Madison","place":["Madison, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung H.","family":"Dang","sequence":"additional","affiliation":[{"name":"Food Science Department, University of Wisconsin\u2013Madison","place":["Madison, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zepeng","family":"Tu","sequence":"additional","affiliation":[{"name":"Food Science Department, University of Wisconsin\u2013Madison","place":["Madison, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, University of Wisconsin\u2013Madison","place":["Madison, 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