TitleAnaplasma phagocytophilum dihydrolipoamide dehydrogenase 1 affects host-derived immunopathology during microbial colonization.
Publication TypeJournal Article
Year of Publication2012
AuthorsChen, G, Severo, MS, Sakhon, OS, Choy, A, Herron, MJ, Felsheim, RF, Wiryawan, H, Liao, J, Johns, JL, Munderloh, UG, Sutterwala, FS, Kotsyfakis, M, Pedra, JHF
JournalInfect Immun
Volume80
Issue9
Pagination3194-205
Date Published2012 Sep
ISSN1098-5522
KeywordsAdult, Anaplasma phagocytophilum, Animals, Dihydrolipoamide Dehydrogenase, Ehrlichiosis, Female, Gene Deletion, Humans, Macrophages, Mice, Mice, Inbred C57BL, Mutagenesis, Insertional, Neutrophils, Spleen, Virulence Factors
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.

DOI10.1128/IAI.00532-12
Alternate JournalInfect. Immun.
PubMed ID22753375
PubMed Central IDPMC3418742
Grant ListK01 CK000101 / CK / NCEZID CDC HHS / United States
R01 AI042792 / AI / NIAID NIH HHS / United States
R01 AI093653 / AI / NIAID NIH HHS / United States