Impairment of gamma interferon signaling in human neutrophils infected with Anaplasma phagocytophilum.
Anaplasma phagocytophilum, the causative agent of tick-borne human granulocytic anaplasmosis (HGA), is an intracellular bacterium which survives and multiplies inside polymorphonuclear neutrophil granulocytes (PMN). Increased bacterial burden in gamma interferon (IFN-gamma)-deficient mice suggested a major role of IFN-gamma in the control of A. phagocytophilum. Here we investigated whether infection of human PMN with A. phagocytophilum impairs IFN-gamma signaling thus facilitating intracellular survival of the bacterium. The secretion of the IFN-gamma-inducible chemokines IP-10/CXCL10 and MIG/CXCL9 was markedly inhibited in infected neutrophils. Molecular analyses revealed that, compared to uninfected PMN, A. phagocytophilum decreased the expression of the IFN-gamma receptor alpha-chain CD119, diminished the IFN-gamma-induced phosphorylation of STAT1, and enhanced the expression of SOCS1 and SOCS3 in PMN. Since IFN-gamma activates various antibacterial effector mechanisms of PMN, the impaired IFN-gamma signaling in infected cells likely contributes to the survival of A. phagocytophilum inside PMN and to HGA disease development.
Institute of Medical Microbiology and Hygiene, University of Luebeck, Ratzeburger Allee 160, Luebeck D-23538, Germany.
Uta
U
Bussmeyer
Arup
A
Sarkar
Kirsten
K
Broszat
Tanja
T
Lüdemann
Sonja
S
Möller
Ger
G
van Zandbergen
Christian
C
Bogdan
Martina
M
Behnen
J Stephen
JS
Dumler
Friederike D
FD
von Loewenich
Werner
W
Solbach
Tamás
T
Laskay
D041081:Anaplasma phagocytophilum / Q000502:physiology*; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D009504:Neutrophils / Q000382:microbiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma