Brucella melitensis triggers time-dependent modulation of apoptosis and down-regulation of mitochondrion-associated gene expression in mouse macrophages.
Brucella spp. are facultative intracellular bacteria that cause brucellosis in humans and other animals. Brucella spp. are taken up by macrophages, and the outcome of the macrophage-Brucella interaction is a basis for establishment of a chronic Brucella infection. Microarrays were used to analyze the transcriptional response of the murine macrophage-like J774.A1 cell line to infection with virulent Brucella melitensis strain 16M. It was found that most significant changes in macrophage gene transcription happened early following infection, and global macrophage gene expression profiles returned to normal between 24 and 48 h postinfection. These findings support the observation that macrophages kill the majority of Brucella cells at the early infection stage, but the surviving Brucella cells are able to avoid macrophage brucellacidal activity inside replicative phagosomes at the later infection stage. At 4 h postinfection, macrophage genes involved in cell growth, metabolism, and responses to endogenous stimuli were down-regulated, while the inflammatory response (e.g., tumor necrosis factor alpha and Toll-like receptor 2), the complement system, the responses to external stimuli, and other immune responses were up-regulated. It is likely that the most active brucellacidal activity happened between 0 and 4 h postinfection. Mitochondrion-associated gene expression, which is involved in protein synthesis and transport, electron transfer, and small-molecule transfer, and many other mitochondrial functions were significantly down-regulated at 4 h postinfection. Although there were both pro- and antiapoptosis effects, B. melitensis 16M appears to inhibit apoptosis of macrophages by blocking release of cytochrome c and production of reactive oxygen species in the mitochondria, thus preventing activation of caspase cascades.
He
Yongqun
Y
Unit for Laboratory Animal Medicine, University of Michigan Medical School, 018 Animal Research Facility, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA. yongqunh@umich.edu
Reichow
Sherry
S
Ramamoorthy
Sheela
S
Ding
Xicheng
X
Lathigra
Raju
R
Craig
Johanna C
JC
Sobral
Bruno W S
BW
Schurig
Gerhardt G
GG
Sriranganathan
Nammalwar
N
Boyle
Stephen M
SM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D017347:Brucella melitensis / Q000472:pathogenicity*; D002006:Brucellosis / Q000235:genetics* / Q000276:immunology*; D020169:Caspases / Q000235:genetics; D002478:Cells, Cultured; D045304:Cytochromes c / Q000235:genetics; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic
D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020169:Caspases