Herpes Simplex Virus Type 1-Induced Encephalitis has an Apoptotic Component Associated with Activation of c-Jun N-Terminal Kinase

Abstract

Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.

The Herpes Simplex Virus Type 2 R1 Protein Kinase (ICP10 PK) Functions as a Dominant Regulator of Apoptosis in Hippocampal Neurons Involving Activation of the ERK Survival Pathway and Upregulation of the Antiapoptotic Protein Bag-1

“…Apoptosis was determined by TUNEL, morphological alterations, caspase activation, and poly(ADP-ribose) polymerase cleavage, a crucial factor in the cell's commitment to undergo apoptosis (48), with a good degree of correlation between the various assays. The specificity of the antibodies used in these studies was previously confirmed in our and other laboratories (3,16,55,63,(66)(67)(68)(73)(74)(75)(76). Normal rabbit serum was negative in all assays.…”

“…These included HSV-2 mutants deleted in the PK (ICP10⌬PK) or RR (ICP10⌬RR) domains of ICP10, transfection with expression vectors for ICP10 (pJW17) or its PK-negative mutant p139 (pJHL15) (3,55,(66)(67)(68)(73)(74)(75)(76), and primary hippocampal cultures that contained Ͼ88% postmitotic neurons, which have definite exons and dendrites, form synapses, are electrically active, and closely resemble neurons in vivo (5). Apoptosis was determined by TUNEL, morphological alterations, caspase activation, and poly(ADP-ribose) polymerase cleavage, a crucial factor in the cell's commitment to undergo apoptosis (48), with a good degree of correlation between the various assays.…”

ICP10PK inhibits calpain-dependent release of apoptosis-inducing factor and programmed cell death in response to the toxin MPP+

“…Previous studies had shown that ICP10PK inhibits caspase-dependent apoptosis triggered by various neurotoxic stimuli, [11][12][13][14][15][16][17]27 but this is the first report that it also inhibits calpaindependent PCD, underscoring its ability to override multiple death programs. The following comments seem pertinent with respect to these findings.…”

“…In this context, it may be significant to point out that the physiopathology of PD was also associated with death programs that were not studied in the present series of experiments, including growth factor depletion (viz nerve growth factor, NGF), 46 activation of the JNK pathway, 35 and glial cell activation and production of proinflammatory cytokines (viz tumor-necrosis factor-a, and interleukin-1b), 46 all of which are also inhibited by ICP10PK. 11,12,14,27 ICP10PK also upregulates XIAP, 12 which was also implicated in PD therapy. 35,47 We conclude that ICP10PK has a broad-spectrum neuroprotective activity, which is characterized by remarkable functional redundancy associated with the activation of survival pathways that can inhibit multiple death programs and modulate neuron-glial cell cross talk.…”

Caspase-3-dependent apoptosis in cardiac myxoma: not associated with human papillomavirus or Epstein–Barr virus

“…31 Caspase-dependent apoptosis is involved in HSV-associated injury, 32 in adrenal cells, neuronal cells, corneal cells, hepatic cells, and dendritic cells as well. [33][34][35][36][37] Recently, the association between cardiac myxoma and HSV-1 has been determined. 7 Thus, we assume that HSV-1 might induce apoptosis in myxoma.…”