Anaplasma phagocytophilum dihydrolipoamide dehydrogenase 1 affects host-derived immunopathology during microbial colonization

Gang Chen, Maiara S. Severo, Olivia S. Sakhon, Anthony Choy, Michael J. Herron, Roderick F. Felsheim, Hilda Wiryawan, Jiayu Liao, Jennifer L. Johns, Ulrike G. Munderloh, Fayyaz S. Sutterwala, Michail Kotsyfakis, Joao H.F. Pedra

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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)-k{cyrillic}B 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.

Original languageEnglish (US)
Pages (from-to)3194-3205
Number of pages12
JournalInfection and immunity
Volume80
Issue number9
DOIs
StatePublished - Sep 2012

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