Histopathological Analysis of Adrenal Glands after Simian Varicella Virus Infection

Abstract

Latent varicella zoster virus (VZV) has been detected in human adrenal glands, raising the possibility of virus-induced adrenal damage and dysfunction during primary infection or reactivation. Rare cases of bilateral adrenal hemorrhage and insufficiency associated with VZV reactivation have been reported. Since there is no animal model for VZV infection of adrenal glands, we obtained adrenal glands from two non-human primates (NHPs) that spontaneously developed varicella from primary simian varicella virus (SVV) infection, the NHP VZV homolog. Histological and immunohistochemical analysis revealed SVV antigen and DNA in the adrenal medulla and cortex of both animals. Adrenal glands were observed to have Cowdry A inclusion bodies, cellular necrosis, multiple areas of hemorrhage, and varying amounts of polymorphonuclear cells. No specific association of SVV antigen with βIII-tubulin-positive nerve fibers was found. Overall, we found that SVV can productively infect NHP adrenal glands, and is associated with inflammation, hemorrhage, and cell death. These findings suggest that further studies are warranted to examine the contribution of VZV infection to human adrenal disease. This study also suggests that VZV infection may present itself as acute adrenal dysfunction with “long-hauler” symptoms of fatigue, weakness, myalgias/arthralgias, and hypotension.

VZV Infection of Primary Human Adrenal Cortical Cells Produces a Proinflammatory Environment without Cell Death

“…The absence of cell death in VZV-infected adrenal cortical cells could be attributed to the time of analysis (longer infection times may lead to cell death) or absence of immune cells that may infiltrate adrenal glands and induce cell death in vivo. Indeed, our histopathological examination of SVV-infected adrenal glands show immune infiltrates, hemorrhage, and cellular necrosis [6]. Alternatively, adrenal cortical cells may be resistant to VZV-induced cell death, implying that they may be a potential reservoir for persistent viral infection.…”

“…Support for VZV's contributions to adrenal dysfunction during primary infection is provided by case reports of individuals developing bilateral adrenal hemorrhage (Waterhouse-Friderichsen Syndrome) associated with varicella [2][3][4][5]. Additionally, in non-human primates (NHP) with spontaneous disseminated simian varicella virus (SVV; the NHP homolog of VZV) infection, adrenal glands contain both SVV DNA and antigen, predominantly in the cortex, associated with Cowdry A inclusion bodies, cellular necrosis, multiple areas of hemorrhage, and varying amounts of polymorphonuclear cells [6]. However, the mechanisms by which VZV affects the adrenal glands are not well-characterized.…”

Effects of very low-calorie ketogenic diet on hypothalamic–pituitary–adrenal axis and renin–angiotensin–aldosterone system

“…According to Kim and Choi, the adrenal cortex synthesizes steroid hormones from cholesterol through a series of biochemical metabolic pathways [ 1 , 2 ]. Furthermore, the adrenal cortex consists of three different cortical zones: the glomerulosa zone, secreting mineralocorticoids such as aldosterone, the intermediate fasciculate zone, secreting glucocorticoids such as cortisol, and the innermost reticularis zone, secreting androgens [ 3 , 4 ], as shown in Fig. 1 , while the medullary area produces epinephrine and norepinephrine as part of the sympathetic nervous system [ 3 , 4 ].…”

Special Issue “Replication and Spread of Alphaherpesviruses”

“…To study this, the authors differentiate human induced pluripotent stem cells (iPSCs) towards the cortical neuron lineage, examining the replication of HSV-1 in various cell stages along the way. A third paper by Niemeyer et al [9] focuses on the potential tropism of varicella-zoster virus (VZV), another human alphaherpesviral pathogen, for the adrenal gland. To examine this, the authors study adrenal gland tissue from non-human primates infected with a simian virus closely related to VZV.…”