Signaling cascades triggered by bacterial metabolic end products during reactivation of Kaposi's sarcoma-associated herpesvirus.
The present studies explore the role of polymicrobial infection in the reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) and analyze signaling pathways activated upon this induction. We hypothesized that activation of the cellular stress-activated mitogen-activated protein kinase (MAPK) p38 pathway would play a key role in the bacterium-mediated disruption of viral latency similar to that of previously reported results obtained with other inducers of gammaherpesvirus lytic replication. KSHV within infected BCBL-1 cells was induced to replicate following exposure to metabolic end products from gram-negative or -positive bacteria that were then simultaneously exposed to specific inhibitors of signal transduction pathways. We have determined that bacterium-mediated induction of lytic KSHV infection is significantly reduced by the inhibition of the p38 MAPK pathway. In contrast, inhibition of the phosphatidylinositol 3-kinase pathway did not impair induction of lytic replication or p38 phosphorylation. Protein kinase C, though activated, was not the major pathway used for bacterium-induced viral reactivation. Furthermore, hyperacetylation of histones 3 and 4 was detected. Collectively, our results show that metabolic end products from these pathogens induce lytic replication of KSHV in BCBL-1 cells primarily via the activation of a stress-activated MAPK pathway. Importantly, we demonstrate for the first time a mechanism by which polymicrobial bacterial infections result in KSHV reactivation and pathogenesis.
Morris
T L
TL
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Arnold
R R
RR
Webster-Cyriaque
J
J
D001421:Bacteria, Anaerobic / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D016967:Fusobacterium nucleatum / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D016966:Porphyromonas gingivalis / Q000502:physiology; D012514:Sarcoma, Kaposi / Q000821:virology*; D015398:Signal Transduction / Q000502:physiology*; D014775:Virus Activation / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology
D017077:Culture Media, Conditioned