title: Anaplasma phagocytophilum dihydrolipoamide dehydrogenase 1 affects host-derived immunopathology during microbial colonization.
abstract: Anaplasma phagocytophilum is a tick-borne rickettsial pathogen that provokes an acute inflammatory response during mammalian infection. The illness caused by A. phagocytophilum, human granulocytic anaplasmosis, occurs irrespective of pathogen load and results instead from host-derived immunopathology. Thus, characterizing A. phagocytophilum genes that affect the inflammatory process is critical for understanding disease etiology. By using an A. phagocytophilum Himar1 transposon mutant library, we showed that a single transposon insertion into the A. phagocytophilum dihydrolipoamide dehydrogenase 1 gene (lpda1 [APH_0065]) affects inflammation during infection. A. phagocytophilum lacking lpda1 revealed enlargement of the spleen, increased splenic extramedullary hematopoiesis, and altered clinicopathological abnormalities during mammalian colonization. Furthermore, LPDA1-derived immunopathology was independent of neutrophil infection and correlated with enhanced reactive oxygen species from NADPH oxidase and nuclear factor (NF)-κB signaling in macrophages. Taken together, these findings suggest the presence of different signaling pathways in neutrophils and macrophages during A. phagocytophilum invasion and highlight the importance of LPDA1 as an immunopathological molecule.
authors: Department of Entomology and Center for Disease Vector Research, University of California-Riverside, Riverside, California, USA.
authors: Gang
authors: G
authors: Chen
authors: Maiara S
authors: MS
authors: Severo
authors: Olivia S
authors: OS
authors: Sakhon
authors: Anthony
authors: A
authors: Choy
authors: Michael J
authors: MJ
authors: Herron
authors: Roderick F
authors: RF
authors: Felsheim
authors: Hilda
authors: H
authors: Wiryawan
authors: Jiayu
authors: J
authors: Liao
authors: Jennifer L
authors: JL
authors: Johns
authors: Ulrike G
authors: UG
authors: Munderloh
authors: Fayyaz S
authors: FS
authors: Sutterwala
authors: Michail
authors: M
authors: Kotsyfakis
authors: Joao H F
authors: JH
authors: Pedra
mesh_terms: D000328:Adult; D041081:Anaplasma phagocytophilum / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity; D000818:Animals; D008058:Dihydrolipoamide Dehydrogenase / Q000276:immunology* / Q000378:metabolism*; D016873:Ehrlichiosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D037521:Virulence Factors / Q000276:immunology* / Q000378:metabolism*
chemical_list: D037521:Virulence Factors; D008058:Dihydrolipoamide Dehydrogenase