{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:21:06Z","timestamp":1790047266540,"version":"4.0.1"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2014,8,1]],"date-time":"2014-08-01T00:00:00Z","timestamp":1406851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            (p)ppGpp responds to nutrient limitation through a global change in gene regulation patterns to increase survival. The stringent response has been implicated in the virulence of several pathogenic bacterial species.\n            <jats:named-content content-type=\"genus-species\">Haemophilus ducreyi<\/jats:named-content>\n            , the causative agent of chancroid, has homologs of both\n            <jats:italic>relA<\/jats:italic>\n            and\n            <jats:italic>spoT<\/jats:italic>\n            , which primarily synthesize and hydrolyze (p)ppGpp in\n            <jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>\n            . We constructed\n            <jats:italic>relA<\/jats:italic>\n            and\n            <jats:italic>relA spoT<\/jats:italic>\n            deletion mutants to assess the contribution of (p)ppGpp to\n            <jats:named-content content-type=\"genus-species\">H. ducreyi<\/jats:named-content>\n            pathogenesis. Both the\n            <jats:italic>relA<\/jats:italic>\n            single mutant and the\n            <jats:italic>relA spoT<\/jats:italic>\n            double mutant failed to synthesize (p)ppGpp, suggesting that\n            <jats:italic>relA<\/jats:italic>\n            is the primary synthetase of (p)ppGpp in\n            <jats:named-content content-type=\"genus-species\">H. ducreyi<\/jats:named-content>\n            . Compared to the parent strain, the double mutant was partially attenuated for pustule formation in human volunteers. The double mutant had several phenotypes that favored attenuation, including increased sensitivity to oxidative stress. The increased sensitivity to oxidative stress could be complemented in\n            <jats:italic>trans<\/jats:italic>\n            . However, the double mutant also exhibited phenotypes that favored virulence. When grown to the mid-log phase, the double mutant was significantly more resistant than its parent to being taken up by human macrophages and exhibited increased transcription of\n            <jats:italic>lspB<\/jats:italic>\n            , which is involved in resistance to phagocytosis. Additionally, compared to the parent, the double mutant also exhibited prolonged survival in the stationary phase. In\n            <jats:named-content content-type=\"genus-species\">E. coli<\/jats:named-content>\n            , overexpression of DksA compensates for the loss of (p)ppGpp; the\n            <jats:named-content content-type=\"genus-species\">H. ducreyi<\/jats:named-content>\n            double mutant expressed higher transcript levels of\n            <jats:italic>dksA<\/jats:italic>\n            than the parent strain. These data suggest that the partial attenuation of the double mutant is likely the net result of multiple conflicting phenotypes.\n          <\/jats:p>","DOI":"10.1128\/iai.01994-14","type":"journal-article","created":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T03:24:29Z","timestamp":1402370669000},"page":"3492-3502","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["A (p)ppGpp-Null Mutant of Haemophilus ducreyi Is Partially Attenuated in Humans Due to Multiple Conflicting Phenotypes"],"prefix":"10.1128","volume":"82","author":[{"given":"Concerta","family":"Holley","sequence":"first","affiliation":[{"name":"Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharanesh","family":"Gangaiah","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate R.","family":"Fortney","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane M.","family":"Janowicz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Ellinger","sequence":"additional","affiliation":[{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Zwickl","sequence":"additional","affiliation":[{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry P.","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley M.","family":"Spinola","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Departments of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"689","volume-title":"Sexually transmitted diseases","author":"Spinola SM","year":"2008","unstructured":"SpinolaSM. 2008. Chancroid and Haemophilus ducreyi, p 689\u2013699. 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