title: Human herpesvirus 6A induces apoptosis of primary human fetal astrocytes via both caspase-dependent and -independent pathways.
abstract: BACKGROUND
  Human herpesvirus 6 (HHV-6) is a T-lymphtropic and neurotropic virus that can infect various types of cells. Sequential studies reported that apoptosis of glia and neurons induced by HHV-6 might act a potential trigger for some central nervous system (CNS) diseases. HHV-6 is involved in the pathogenesis of encephalitis, multiple sclerosis (MS) and fatigue syndrome. However, the mechanisms responsible for the apoptosis of infected CNS cells induced by HHV-6 are poorly understood. In this study, we investigated the cell death processes of primary human fetal astrocytes (PHFAs) during productive HHV-6A infection and the underlying mechanisms.
  
  
  RESULTS
  HHV-6A can cause productive infection in primary human fetal astrocytes. Annexin V-PI staining and electron microscopic analysis indicated that HHV-6A was an inducer of apoptosis. The cell death was associated with activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP), which is known to be an important substrate for activated caspase-3. Caspase-8 and -9 were also significantly activated in HHV-6A-infected cells. Moreover, HHV-6A infection led to Bax up-regulation and Bcl-2 down-regulation. HHV-6A infection increased the release of Smac/Diablo, AIF and cytochrome c from mitochondria to cytosol, which induced apoptosis via the caspase-dependent and -independent pathways. In addition, we also found that anti-apoptotic factors such as IAPs and NF-κB decreased in HHV-6A infected PHFAs.
  
  
  CONCLUSIONS
  This is the first demonstration of caspase-dependent and -independent apoptosis in HHV-6A-infected glial cells. These findings would be helpful in understanding the mechanisms of CNS diseases caused by HHV-6.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Gu
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Zhang
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: Feng
authors.forename: Chuan-Lin
authors.initials: CL
authors.lastname: Ding
authors.forename: Jing
authors.initials: J
authors.lastname: Chi
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Guo
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Hu
mesh_terms: D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000821:virology*; D005786:Gene Expression Regulation; D015654:Herpesvirus 6, Human / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; D016328:NF-kappa B; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases