Autophagy has recently been demonstrated in both cultured cells infected with varicella- zoster virus (VZV) as well as in a human zoster vesicle. The presence of punctate autophagosomes in a zoster skin vesicle firmly established that autophagy (macroautophagy) is a relevant biological process during the natural history of disease caused by this herpesvirus. Of importance, we have carried out sufficient preliminary studies to document that autophagy induced by VZV infection does not resemble HSV-induced autophagy. First of all, the VZV genome lacks a homolog of the HSV ICP 34.5 gene. Secondly, we have now shown by two different methods that VZV infection quickly induces marked ER stress, an event not known to occur in the HSV system. Therefore, the re-stated central hypothesis for this proposal is that ER stress is a critical component of VZV infection, that ER stress is related to an over abundance of misfolded VZV glycoproteins in the ER, and that ER-associated degradation and autophagy are consequences that relieve ER stress. These events allow the infected cell to survive longer, to avoid apoptosis, and in that sense can be considered pro-viral. The Research Plan to test this hypothesis involves three Specific Aims.
Aim 1 is called Induction of autophagy as a consequence of VZV induced ER stress.
Aim 2 is called Activation of the unfolded protein response (UPR) by VZV induced ER stress.
Aim 3, which involves the A. Arvin laboratory, includes Studies of autophagy and ER stress in the SCID-hu mouse model, following infection with various recombinant mutated VZV genomes. In our Research Plan, we will continue prior investigations with an expanded experimental approach directed toward the three sensor pathways that lead from ER stress to the UPR (IRE1, ATF6 and PERK). We have already detected four proteins associated with the UPR in VZV infected cells, including BiP (HSPA5), HSPA8, HSPD1 and PPIA: peptidyl-propyl-cis-trans-isomerase). More recently we have detected the spliced form of XBP1 (X-Box binding protein) in VZV infected cells, another marker of the UPR. The final approach will include animal experiments with already prepared recombinant viruses containing numerous gE mutations. The phenotypes of these mutant viruses have already been determined in both cell culture and the SCID mouse model. Thus the above experimental plan will determine the relative importance of ER stress and autophagy in the cellular response to VZV infection. The results are relevant not only to our understanding of varicella vaccination but also the debilitating zoster-related illness called post-herpetic neuralgia.
Varicella zoster virus is the first human herpesvirus to be attenuated for a vaccine to prevent chickenpox and also herpes zoster. Questions remain about the mechanisms of protection, especially for older adults who receive the vaccine to prevent shingles.
|Halling, Geoffrey C; Grose, Charles (2016) Focal herpes zoster encephalitis without a rash: diagnostic confusion between astrogliosis and low-grade glioma. Expert Rev Anti Infect Ther 14:1109-1111|
|Carpenter, John E; Clayton, Amy C; Halling, Kevin C et al. (2016) Defensive Perimeter in the Central Nervous System: Predominance of Astrocytes and Astrogliosis during Recovery from Varicella-Zoster Virus Encephalitis. J Virol 90:379-91|
|Grose, Charles (2016) Biological Plausibility of a Link Between Arterial Ischemic Stroke and Infection With Varicella-Zoster Virus or Herpes Simplex Virus. Circulation 133:695-7|
|Grose, Charles; Johanson, Donald C (2016) Transmission of Cytomegalovirus, Epstein-Barr Virus, and Herpes Simplex Virus Infections: From the Lucy Australopithecus Epoch to Modern-Day Netherlands. J Pediatr 170:9-10|
|Buckingham, Erin M; Jarosinski, Keith W; Jackson, Wallen et al. (2016) Exocytosis of Varicella-Zoster Virus Virions Involves a Convergence of Endosomal and Autophagy Pathways. J Virol 90:8673-85|
|Grose, Charles; Buckingham, Erin M; Jackson, Wallen et al. (2015) The pros and cons of autophagic flux among herpesviruses. Autophagy 11:716-7|
|Xing, Yi; Oliver, Stefan L; Nguyen, TuongVi et al. (2015) A site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL. Proc Natl Acad Sci U S A 112:6056-61|
|Lavi, Ehud; Gilden, Don; Nagel, Maria et al. (2015) Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 85:1914-5|
|Liu, Grace; Fennelly, Glenn; Kazacos, Kevin R et al. (2015) Baylisascaris procyonis and Herpes Simplex Virus 2 Coinfection Presenting as Ocular Larva Migrans with Granuloma Formation in a Child. Am J Trop Med Hyg 93:612-4|
|Kelley, James; Tristram, Debra; Yamada, Masaki et al. (2015) Failure of a Single Varicella Vaccination to Protect Children With Cancer From Life-Threatening Breakthrough Varicella. Pediatr Infect Dis J 34:1027-9|
Showing the most recent 10 out of 29 publications