title: Stat1 negatively regulates immune-mediated injury with Anaplasma phagocytophilum infection.
abstract: 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-γ 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, >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-infected Stat1 KO mice compared with wild-type mice. The leukocyte infiltrates in the livers and spleens of A. phagocytophilum-infected Stat1 KO mice also contained expansions in neutrophil and monocyte/macrophage populations. Importantly, A. phagocytophilum-infected 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.
authors.affiliation: Department of Animal Biotechnology, College of Animal Science, Kyungpook National University, Sangju 742-711, Republic of Korea; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Kyoung-Seong
authors.initials: KS
authors.lastname: Choi
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Biomedical Sciences, Ross University School of Veterinary Medicine, St. Kitts and Nevis, West Indies;
authors.forename: Diana G
authors.initials: DG
authors.lastname: Scorpio
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pathology, University of Maryland, Baltimore, MD 21201; and Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201 sdumler@som.umaryland.edu.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Dumler
mesh_terms: D041081:Anaplasma phagocytophilum / Q000276:immunology*; D000712:Anaplasmosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015870:Gene Expression; D056747:Immunomodulation; D008099:Liver / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012720:Severity of Illness Index; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse