ASC/PYCARD and caspase-1 regulate the IL-18/IFN-gamma axis during Anaplasma phagocytophilum infection.
Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within neutrophils and can cause fever, pancytopenia, or death. IFN-gamma plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN-gamma production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN-gamma axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and asc-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN-gamma levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4+ T cell-mediated IFN-gamma after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN-gamma production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN-gamma-mediated control of A. phagocytophilum infection.
Pedra
Joao H F
JH
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Sutterwala
Fayyaz S
FS
Sukumaran
Bindu
B
Ogura
Yasunori
Y
Qian
Feng
F
Montgomery
Ruth R
RR
Flavell
Richard A
RA
Fikrig
Erol
E
D020816:Amino Acid Motifs; D000709:Anaplasma / Q000276:immunology*; D000712:Anaplasmosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D020382:Interleukin-18; C512299:Ipaf protein, mouse; D007371:Interferon-gamma; D020170:Caspase 1