{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:47:04Z","timestamp":1791294424826,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human granulocytic anaplasmosis (HGA) is caused by the obligate intracellular bacterium Anaplasma phagocytophilum. Our data previously demonstrated that A. phagocytophilum induces an immunopathologic response by activating IFN-\u03b3 production through the Stat1 signaling pathway. In this study, we investigated the broader role of Stat1 signaling in the host response to infection with A. phagocytophilum. In Stat1 knockout (KO) compared with wild-type mice, A. phagocytophilum infection was more highly pathogenic as characterized by the unanticipated development of clinical signs in mice including markedly increased splenomegaly, more severe inflammatory splenic and hepatic histopathology, &amp;gt;100-fold higher blood and splenic bacterial loads, and more elevated proinflammatory cytokine\/chemokine responses in serum. CD4+ and CD8+ T lymphocyte populations were significantly expanded in spleens of A. phagocytophilum\u2013infected Stat1 KO mice compared with wild-type mice. The leukocyte infiltrates in the livers and spleens of A. phagocytophilum\u2013infected Stat1 KO mice also contained expansions in neutrophil and monocyte\/macrophage populations. Importantly, A. phagocytophilum\u2013infected Stat1 KO mice did not demonstrate induction of inducible NO synthase in splenocytes. These results show that Stat1 plays an important role in controlling bacterial loads but also by unexpectedly providing an undefined mechanism for dampening of the immunopathologic response observed with A. phagocytophilum infection.<\/jats:p>","DOI":"10.4049\/jimmunol.1401381","type":"journal-article","created":{"date-parts":[[2014,10,11]],"date-time":"2014-10-11T04:13:50Z","timestamp":1413000830000},"page":"5088-5098","source":"Crossref","is-referenced-by-count":15,"title":["Stat1 Negatively Regulates Immune-Mediated Injury with <i>Anaplasma phagocytophilum<\/i> Infection"],"prefix":"10.1093","volume":"193","author":[{"given":"Kyoung-Seong","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Animal Biotechnology, College of Animal Science, Kyungpook National University , Sangju 742-711 ,","place":["Republic of Korea"]},{"name":"Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana G","family":"Scorpio","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"},{"name":"Department of Biomedical Sciences, Ross University School of Veterinary Medicine , St. Kitts and Nevis ,","place":["West Indies"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Stephen","family":"Dumler","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University School of Medicine , Baltimore, MD 21205"},{"name":"Department of Pathology, University of Maryland , Baltimore, MD 21201"},{"name":"Department of Microbiology and Immunology, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,11,15]]},"reference":[{"key":"2025030707441914500_r1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1574-695X.2011.00909.x","article-title":"The biological basis of severe outcomes in Anaplasma phagocytophilum infection","volume":"64","author":"Dumler","year":"2012","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"2025030707441914500_r2","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1086\/313948","article-title":"Human granulocytic ehrlichiosis","volume":"31","author":"Bakken","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"2025030707441914500_r3","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1086\/518146","article-title":"Ehrlichioses in humans: epidemiology, clinical presentation, diagnosis, and treatment","volume":"45","author":"Dumler","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"2025030707441914500_r4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4269\/ajtmh.2011.10-0613","article-title":"Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000-2007","volume":"85","author":"Dahlgren","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2025030707441914500_r5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1086\/518834","article-title":"Human granulocytic anaplasmosis and macrophage activation","volume":"45","author":"Dumler","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"2025030707441914500_r6","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1086\/315206","article-title":"Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model","volume":"181","author":"Martin","year":"2000","journal-title":"J. Infect. Dis."},{"key":"2025030707441914500_r7","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/S0002-9440(10)64145-4","article-title":"Immunopathology and ehrlichial propagation are regulated by interferon-gamma and interleukin-10 in a murine model of human granulocytic ehrlichiosis","volume":"158","author":"Martin","year":"2001","journal-title":"Am. J. Pathol."},{"key":"2025030707441914500_r8","first-page":"55","article-title":"Role of reactive nitrogen species in development of hepatic injury in a C57bl\/6 mouse model of human granulocytic anaplasmosis","volume":"56","author":"Browning","year":"2006","journal-title":"Comp. Med."},{"key":"2025030707441914500_r9","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1086\/386284","article-title":"Anaplasma phagocytophilum ligation to toll-like receptor (TLR) 2, but not to TLR4, activates macrophages for nuclear factor-kappa B nuclear translocation","volume":"189","author":"Choi","year":"2004","journal-title":"J. Infect. Dis."},{"key":"2025030707441914500_r10","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1128\/CVI.00092-06","article-title":"Innate immune response to Anaplasma phagocytophilum contributes to hepatic injury","volume":"13","author":"Scorpio","year":"2006","journal-title":"Clin. Vaccine Immunol."},{"key":"2025030707441914500_r11","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1128\/IAI.68.4.1827-1833.2000","article-title":"Gamma interferon dominates the murine cytokine response to the agent of human granulocytic ehrlichiosis and helps to control the degree of early rickettsemia","volume":"68","author":"Akkoyunlu","year":"2000","journal-title":"Infect. Immun."},{"key":"2025030707441914500_r12","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.femsim.2004.06.001","article-title":"Interferon-\u03b3 deficiency reveals that 129Sv mice are inherently more susceptible to Anaplasma phagocytophilum than C57BL\/6 mice","volume":"42","author":"Wang","year":"2004","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"2025030707441914500_r13","doi-asserted-by":"crossref","first-page":"e23820","DOI":"10.4161\/jkst.23820","article-title":"The regulation of inflammation by interferons and their STATs","volume":"2","author":"Rauch","year":"2013","journal-title":"JAK-STAT"},{"key":"2025030707441914500_r14","doi-asserted-by":"crossref","first-page":"6932","DOI":"10.1128\/JVI.07147-11","article-title":"Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus","volume":"86","author":"Hofer","year":"2012","journal-title":"J. Virol."},{"key":"2025030707441914500_r15","doi-asserted-by":"crossref","first-page":"e27521","DOI":"10.4161\/jkst.27521","article-title":"STAT2 and IRF9: Beyond ISGF3","volume":"2","author":"Fink","year":"2013","journal-title":"JAK-STAT"},{"key":"2025030707441914500_r16","doi-asserted-by":"crossref","first-page":"e1002763","DOI":"10.1371\/journal.ppat.1002763","article-title":"Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection","volume":"8","author":"Kernbauer","year":"2012","journal-title":"PLoS Pathog."},{"key":"2025030707441914500_r17","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/1348-0421.12023","article-title":"Anaplasma phagocytophilum, interferon gamma production and Stat1 signaling","volume":"57","author":"Choi","year":"2013","journal-title":"Microbiol. Immunol."},{"key":"2025030707441914500_r18","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1128\/CVI.05034-11","article-title":"Dexamethasone-induced cytokine changes associated with diminished disease severity in horses infected with Anaplasma phagocytophilum","volume":"18","author":"Davies","year":"2011","journal-title":"Clin. Vaccine Immunol."},{"key":"2025030707441914500_r19","first-page":"963","article-title":"CXCR2 blockade influences Anaplasma phagocytophilum propagation but not histopathology in the mouse model of human granulocytic anaplasmosis","volume":"11","author":"Scorpio","year":"2004","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"2025030707441914500_r20","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/2049-632X.12111","article-title":"Comparison and characterization of granulocyte cell models for Anaplasma phagocytophilum infection","volume":"71","author":"Rennoll-Bankert","year":"2014","journal-title":"Pathog Dis"},{"key":"2025030707441914500_r21","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1111\/j.1574-695X.2007.00214.x","article-title":"Msp2 variation in Anaplasma phagocytophilum in vivo does not stimulate T cell immune responses or interferon-gamma production","volume":"49","author":"Choi","year":"2007","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"2025030707441914500_r22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1600-065X.2008.00707.x","article-title":"Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms","volume":"226","author":"Hu","year":"2008","journal-title":"Immunol. Rev."},{"key":"2025030707441914500_r23","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4049\/jimmunol.172.1.457","article-title":"STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis","volume":"172","author":"Lieberman","year":"2004","journal-title":"J. Immunol."},{"key":"2025030707441914500_r24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1620\/tjem.202.41","article-title":"STAT1 knockout mice are highly susceptible to pulmonary mycobacterial infection","volume":"202","author":"Sugawara","year":"2004","journal-title":"Tohoku J. Exp. Med."},{"key":"2025030707441914500_r25","doi-asserted-by":"crossref","first-page":"4783","DOI":"10.4049\/jimmunol.179.7.4783","article-title":"ASC\/PYCARD and caspase-1 regulate the IL-18\/IFN-gamma axis during Anaplasma phagocytophilum infection","volume":"179","author":"Pedra","year":"2007","journal-title":"J. Immunol."},{"key":"2025030707441914500_r26","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1111\/j.1574-695X.2007.00270.x","article-title":"IL-12\/23p40-dependent clearance of Anaplasma phagocytophilum in the murine model of human anaplasmosis","volume":"50","author":"Pedra","year":"2007","journal-title":"FEMS Immunol. Med. 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