Tula hantavirus infection of Vero E6 cells induces apoptosis involving caspase 8 activation.
Hantaviruses are known to cause two severe human diseases: haemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. The mechanisms of pathogenesis of these two diseases are progressively becoming understood. Recently, two hantaviruses, Hantaan and Prospect Hill were reported to cause programmed cell death of Vero E6 cells. This study shows that Tula hantavirus (TULV) infection efficiently triggers an apoptotic programme in infected Vero E6 cells, and that the replication of TULV is required for the activation of caspase 3 and the cleavage of poly (ADP-ribose) polymerase, two molecular hallmarks of apoptosis. The enforced treatment of infected Vero E6 cells with tumour necrosis factor alpha (TNF-alpha), but not interferon alpha (IFN-alpha), advanced the time course of apoptosis. Furthermore, caspase 8 was activated on day 4 post-infection, the same day when caspase 3 was activated. TNF receptor 1 was induced during a late stage of TULV infection. These data suggest that, unlike during influenza A virus infection, TNF-alpha, but not type I IFN-alpha/beta, may contribute significantly to apoptosis in a synergistic manner with TULV propagation. Interestingly, pretreatment with a broad-spectrum caspase inhibitor, z-VAD-fmk, efficiently inhibited apoptosis of TULV-infected Vero E6 cells. Taken together, these results suggest that TULV replication initiates a typical apoptotic programme involving caspase 8 activation.
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Xiao-Dong
XD
Li
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Sami
S
Kukkonen
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Olli
O
Vapalahti
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Alexander
A
Plyusnin
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Hilkka
H
Lankinen
Department of Virology, Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland.
Antti
A
Vaheri
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006476:Orthohantavirus / Q000472:pathogenicity* / Q000502:physiology; D015151:Immunoblotting; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases