{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T01:53:01Z","timestamp":1783389181427,"version":"3.54.6"},"reference-count":85,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institutes of Health\u2013National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI167857"],"award-info":[{"award-number":["R01 AI167857"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institutes of Health\u2013National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI179778"],"award-info":[{"award-number":["R01 AI179778"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institutes of Health\u2013National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["F32 AI174656A1"],"award-info":[{"award-number":["F32 AI174656A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Scrub typhus is an emerging chigger-borne disease caused by the obligate intracellular bacterium Orientia tsutsugamushi. Necroptosis is a form of programmed cell death (PCD) mediated by RIPK3 (serine\/threonine kinase receptor interacting protein 3) and its downstream effector MLKL (mixed-lineage kinase domain-like). While O. tsutsugamushi modulates apoptosis, another form of PCD, its interplay with necroptosis is unknown. Much of Orientia pathobiology is linked to its ankyrin repeat (AR)-containing effectors (Anks). Two of these, Ank1 and Ank6, share similarities with the cowpox AR protein, vIRD (viral inducer of RIPK3 degradation) that prevents necroptosis. Here, we show that Ank1 and Ank6 reduce RIPK3 cellular levels although not as robustly as and mechanistically distinct from vIRD. Orientia infection lowers RIPK3 amounts and does not elicit necroptosis in endothelial cells. In HeLa cells ectopically expressing RIPK3, Orientia fails to inhibit RIPK3 and MLKL phosphorylation as well as cell death. MLKL colocalization with Orientia or Listeria\u00a0monocytogenes, another intracytoplasmic pathogen, was not observed. Thus, O. tsutsugamushi reduces cellular levels of RIPK3 and does not elicit necroptosis but cannot inhibit this PCD pathway once it is induced. This study is a first step toward understanding how the relationship between Orientia and necroptosis contributes to scrub typhus pathogenesis.<\/jats:p>","DOI":"10.3390\/pathogens14050478","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T10:27:41Z","timestamp":1747218461000},"page":"478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Orientia tsutsugamushi Modulates RIPK3 Cellular Levels but Does Not Inhibit Necroptosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6000-6285","authenticated-orcid":false,"given":"Thomas E.","family":"Siff","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0299-7380","authenticated-orcid":false,"given":"Paige E.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Armistead","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9622-9157","authenticated-orcid":false,"given":"Steven J.","family":"Rolland","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3350-0218","authenticated-orcid":false,"given":"Herv\u00e9","family":"Agaisse","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2778-5066","authenticated-orcid":false,"given":"Jason A.","family":"Carlyon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41418-018-0172-x","article-title":"Necroptosis in anti-viral inflammation","volume":"26","author":"Nailwal","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_2","first-page":"85","article-title":"Manipulation of Host Cell Death Pathways by Herpes Simplex Virus","volume":"442","author":"He","year":"2023","journal-title":"Curr. 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