Autophagosome Formation during Varicella-Zoster Virus Infection following Endoplasmic Reticulum Stress and the Unfolded Protein Response

Abstract

Autophagy is a recently recognized component of the life cycle of varicella-zoster virus (VZV).We have documented abundant autophagosome formation in skin vesicles (final site of virion assembly) from randomly selected cases of varicella and zoster. The fact that autophagy was an early event in the VZV replication cycle was documented by finding infected vesicle cells with the VZV IE62 protein confined to the nucleus. Next, we pursued studies in VZV-infected cultured cells to define whether autophagy was preceded by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). First, we demonstrated that autophagosome formation in infected cells closely resembled that seen after treatment of cells with tunicamycin, a potent initiator of ER stress. Second, we demonstrated a marked expansion of ER size in both VZV-infected cells and cells transfected with the predominant VZV glycoprotein complex gE/gI. An enlarged ER is critical evidence of ER stress, which in turn is relieved by the UPR. To this end, we documented the UPR by detecting the alternatively spliced form of the XBP1 protein as well as CHOP (C/EBP homologous protein), both transcriptional activators of other UPR genes in an ER stress-dependent manner. Because VZV does not encode inhibitors of autophagy, the above results suggested that autophagy was a common event in VZV-infected cells and that it was provoked at least in part by ER stress secondary to overly abundant VZV glycoprotein biosynthesis, which led to UPR activation in an attempt to maintain cellular homeostasis.Varicella-zoster virus (VZV) is a human pathogen that causes chicken pox (varicella) and shingles (zoster) (55). Zoster is the disease associated with reactivation of latent VZV in the elderly. The virus exists as a spherical particle approximately 200 nm in diameter, including a 125-kb DNA genome enclosed in an icosahedral capsid which is itself surrounded by an amorphous shell of proteins called the tegument and an outer lipid envelope containing viral glycoproteins (9). The most prominent viral glycoprotein is called gE and is part of the gE/gI complex (20,22). Within a few days after infection, viral replication leads to the assembly of nascent viral particles in the head and neck region. A viremia ensues within T lymphocytes, after which viral particles exit the capillaries and replicate within the epidermis to cause the characteristic vesicular rash (28). The skin vesicle is considered to be the final site of assembly and envelopment of the mature VZ virion (52). Relatively little is known about the innate immune response within the cutaneous microenvironment (2).How a cell responds to viral infection and in turn how the virus attempts to moderate that response have been a topic of renewed research. One such response of the host cell is to increase macroautophagy (29). Macroautophagy is a catabolic process by which whole or parts of organelles are sequestrated into double-membraned autophagosomes in the cytoplasm and then degraded when the autophagosomes fuse with ly...

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

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Autophagy in physiological and pathological processes – selected aspects

“…The data on RSV virus (respiratory syncytial virus) showed that autophagy is pivotal in dendritic cells (Morris et al 2011). Moreover, the observations of varicella and zoster virus (Herpesviridae) as well as Herpes simplex virus are the proof of the importance of autophagy in replication of those viruses, as autophagosomes were found as a part of skin changes formation, typical symptoms of infection with the aboves (Carpenter et al 2011, Wiwaran et al 2012.…”

Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection

“…In early experiments, we documented the presence of autophagosomes in skin vesicles from immunocompetent children with varicella or adults with herpes zoster (15,16). To confirm that the autophagy seen in the VZV-infected skin xenografts in SCID mice, which lack adaptive immune responses, recapitulated the response seen in human skin vesicles from children with varicella, we performed a direct comparison.…”