Role for tumor necrosis factor alpha in murine cytomegalovirus transcriptional reactivation in latently infected lungs.
Interstitial pneumonia is a major clinical manifestation of primary or recurrent cytomegalovirus (CMV) infection in immunocompromised recipients of a bone marrow transplant. In a murine model, lungs were identified as a prominent site of CMV latency and recurrence. Pulmonary latency of murine CMV is characterized by high viral genome burden and a low incidence of variegated immediate-early (IE) gene expression, reflecting a sporadic activity of the major IE promoters (MIEPs) and enhancer. The enhancer-flanking promoters MIEP1/3 and MIEP2 are switched on and off during latency in a ratio of approximately 2:1. MIEP1/3 latency-associated activity generates the IE1 transcript of the ie1/3 transcription unit but not the alternative splicing product IE3 that encodes the essential transactivator of early gene expression. Splicing thus appeared to be an important checkpoint for maintenance of latency. In accordance with previous work of others, we show here that signaling by the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) activates IE1/3 transcription in vivo. As an addition to current knowledge, Poisson distribution analysis revealed an increased incidence of IE1/3 transcriptional events as well as a higher amount of transcripts per event. Notably, TNF-alpha promoted the splicing to IE3 transcripts, but transcription did not proceed to the M55/gB early gene. Moreover, the activated transcriptional state induced by TNF-alpha did not predispose latently infected mice to a higher incidence of virus recurrence after hematoablative treatment. In conclusion, TNF-alpha is an important inductor of IE gene transcriptional reactivation, whereas early genes downstream in the viral replicative cycle appear to be the rate-limiting checkpoint(s) for virus recurrence.
Simon
Christian O
CO
Institute for Virology, Johannes Gutenberg University, Mainz, Germany.
Seckert
Christof K
CK
Dreis
Doris
D
Reddehase
Matthias J
MJ
Grzimek
Natascha K A
NK
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000821:virology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014185:Transplantation, Isogeneic / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency
C088645:IE1 protein, cytomegalovirus; C088646:IE3 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins