A novel link between stress and human cytomegalovirus (HCMV) infection: sympathetic hyperactivity stimulates HCMV activation.
Recently, inflammatory mediators such as TNFalpha were identified as triggering active human cytomegalovirus (HCMV) infection. Here, we demonstrate that a highly stressful event in the absence of systemic inflammation, as observed in patients with acute myocardial infarction, leads to the development of an active HCMV infection in latently infected patients. Elucidating the molecular mechanism of virus activation, we could show that catecholamines directly stimulate the HCMV immediate-early (IE) enhancer/promoter in monocytic cells via beta-2 adrenergic receptors. Subsequent activation of the cAMP/PK-A-signaling pathway results in enhanced synthesis and binding of the transcription factor CREB-1/ATF-1 to the cAMP-responsive elements within the IE enhancer. Epinephrine also enhanced HCMV gene expression in infected THP-1 cells by about 50% in three of four experiments. These data suggest that HCMV, like HSV-1 and VZV, can be (re)activated under stress conditions.
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Department of Medical Virology, Humboldt University, Berlin, D-10098, Germany. susanna.proesch@charite.de
Wendt
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CE
Reinke
P
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Priemer
C
C
Oppert
M
M
Krüger
D H
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Volk
H D
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Döcke
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D051697:Activating Transcription Factor 1; D000328:Adult; D000368:Aged; D002395:Catecholamines / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003587:Cytomegalovirus / Q000201:enzymology / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology*; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D013312:Stress, Physiological / Q000201:enzymology / Q000821:virology*; D013564:Sympathetic Nervous System / Q000821:virology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D014775:Virus Activation
D051697:Activating Transcription Factor 1; C115163:CREB1 protein, human; D002395:Catecholamines; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D018343:Receptors, Adrenergic, beta-2; D014157:Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine