{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:30:21Z","timestamp":1777321821396,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009339","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000}}],"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health-National Institute of Allergy and Infectious Diseases","award":["R01-AI123346"],"award-info":[{"award-number":["R01-AI123346"]}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20PRE35210610"],"award-info":[{"award-number":["20PRE35210610"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, <jats:italic>Orientia tsutsugamushi<\/jats:italic>, which invades phagocytes and endothelial cells <jats:italic>in vivo<\/jats:italic> and diverse tissue culture cell types <jats:italic>in vitro<\/jats:italic>. The ability of <jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic> to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-\u03baB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and I\u03baB\u03b1 sequester the NF-\u03baB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-\u03baB via TNF\u03b1 involves IKK\u03b2-mediated serine phosphorylation of I\u03baB\u03b1 and p105, which leads to their degradation and enables NF-\u03baB nuclear translocation. A portion of p105 is also processed into p50. <jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic> impairs NF-\u03baB translocation into the nucleus, but how it does so is incompletely defined.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Principal findings<\/jats:title>\n<jats:p>Western blot, densitometry, and quantitative RT-PCR analyses of <jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic> infected host cells were used to determine if the pathogen\u2019s ability to inhibit NF-\u03baB is linked to modulation of p105. Results demonstrate that p105 levels are elevated several-fold in <jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic> infected HeLa and RF\/6A cells with only a nominal increase in p50. The <jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic>-stimulated increase in p105 is bacterial dose- and protein synthesis-dependent, but does not occur at the level of host cell transcription. While TNF\u03b1-induced phosphorylation of p105 serine 932 proceeds unhindered in infected cells, p105 levels remain elevated and NF-\u03baB p65 is retained in the cytoplasm.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p><jats:italic>O<\/jats:italic>. <jats:italic>tsutsugamushi<\/jats:italic> specifically stabilizes p105 to inhibit the canonical NF-\u03baB pathway, which advances understanding of how it counters host immunity to establish infection.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0009339","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T07:41:12Z","timestamp":1618558872000},"page":"e0009339","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Orientia tsutsugamushi modulates cellular levels of NF-\u03baB inhibitor p105"],"prefix":"10.1371","volume":"15","author":[{"given":"Tanaporn","family":"Wangsanut","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3462-8985","authenticated-orcid":true,"given":"Katelynn R.","family":"Brann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0783-2948","authenticated-orcid":true,"given":"Haley E.","family":"Adcox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2778-5066","authenticated-orcid":true,"given":"Jason A.","family":"Carlyon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"issue":"1","key":"pntd.0009339.ref001","article-title":"A Review of Scrub Typhus (Orientia tsutsugamushi and 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