Tumor necrosis factor receptor-1-induced neuronal death by TRADD contributes to the pathogenesis of Japanese encephalitis.
While a number of studies have documented the neurotropism of Japanese encephalitis virus (JEV), little is known regarding the molecular mechanism of neuronal death following viral infection. The tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) has been suggested to be the crucial signal adaptor that mediates all intracellular responses from TNFR-1. Using mouse (Neuro2a) and human (SK-N-SH) neuroblastoma cell lines, we have shown that the altered expression of TNFR-1 and TRADD following JEV infection regulates the downstream apoptotic cascades. Activation of TRADD led to mitochondria-mediated neuronal apoptosis. As TRADD-knockout animals or deficient cell lines are unavailable, it has been difficult to definitively address the physiological role of TRADD in diseases pathology following JEV infection. We circumvented this problem by silencing TRADD expression with small-interfering RNA (siRNA) and have found that TRADD is required for TNFR-1-initiated neuronal apoptosis following in vitro infection with JEV. Interestingly, siRNA against TRADD also decreased the viral load in Neuro2a cells. Furthermore, siRNA against TRADD increased the survival of JEV-infected mice by altering the expression of pro apoptotic versus antiapoptotic molecules. These studies show that the engagement of TNFR-1 and TRADD following JEV infection plays a crucial role in neuronal apoptosis.
National Brain Research Centre, Manesar, Haryana, India.
Vivek
V
Swarup
Sulagna
S
Das
Soumya
S
Ghosh
Anirban
A
Basu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004672:Encephalitis, Japanese / Q000473:pathology*; D004789:Enzyme Activation / Q000502:physiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053199:TNF Receptor-Associated Death Domain Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D014343:Trypan Blue; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D014343:Trypan Blue