Pathology of the human spinal ganglia in varicella-zoster virus infection

105

Varicella-zoster virus (VZV) is responsible for both varicella (chickenpox) and herpes zoster (shingles). During varicella, the virus establishes latency within the sensory ganglia and can reactivate to cause herpes zoster, but the immune responses that occur in ganglia during herpes zoster have not previously been defined. We examined ganglia obtained from individuals who, at the time of death, had active herpes zoster. Ganglia innervating the site of the cutaneous herpes zoster rash showed evidence of necrosis, secondary to vasculitis, or localized hemorrhage. Despite this, there was limited evidence of VZV antigen expression, although a large inflammatory infiltrate was observed. Characterization of the infiltrating T cells showed a large number of infiltrating CD4؉ T cells and cytolytic CD8 ؉ T cells. Many of the infiltrating T cells were closely associated with neurons within the reactivated ganglia, yet there was little evidence of T cell-induced neuronal apoptosis. Notably, an upregulation in the expression of major histocompatibility complex class I (MHC-I) and MHC-II molecules was observed on satellite glial cells, implying these cells play an active role in directing the immune response during herpes zoster. This is the first detailed characterization of the interaction between T cells and neuronal cells within ganglia obtained from patients suffering herpes zoster at the time of death and provides evidence that CD4؉ and cytolytic CD8 ؉ T cell responses play an important role in controlling VZV replication in ganglia during active herpes zoster. IMPORTANCEVZV is responsible for both varicella (chickenpox) and herpes zoster (shingles). During varicella, the virus establishes a life-long dormant infection within the sensory ganglia and can reawaken to cause herpes zoster, but the immune responses that occur in ganglia during herpes zoster have not previously been defined. We examined ganglia obtained from individuals who, at the time of death, had active herpes zoster. We found that specific T cell subsets are likely to play an important role in controlling VZV replication in ganglia during active herpes zoster.

Section: Discussionsupporting

confidence: 83%

“…Previous histological studies of ganglia from patients with herpes zoster close to the time of death noted necrosis in part or the whole of the ganglia, with some hemorrhage and lymphocytic infiltration (27)(28)(29)(30)(31)(32). Some cases also showed vascular involvement with perivascular lymphocytic cuffing and thrombosis noted (28,31).…”

Section: Discussionmentioning

confidence: 96%

Analysis of T Cell Responses during Active Varicella-Zoster Virus Reactivation in Human Ganglia

Steain

Sutherland

Rodriguez

et al. 2014

105

“…Thus, a review of the literature revealed only 7 publications that have reported any such examination over the past 100-plus years, and those studies were restricted to basic histological observations (14,18,27,47,52,69,70). Our study provides the first detailed characterization of the repertoire of FIG.…”

Section: Discussionmentioning

confidence: 97%

Characterization of the Host Immune Response in Human Ganglia after Herpes Zoster

Gowrishankar

Steain

Cunningham

et al. 2010

Varicella-zoster virus (VZV) causes varicella (chicken pox) and establishes latency in ganglia, from where it reactivates to cause herpes zoster (shingles), which is often followed by postherpetic neuralgia (PHN), causing severe neuropathic pain that can last for years after the rash. Despite the major impact of herpes zoster and PHN on quality of life, the nature and kinetics of the virus-immune cell interactions that result in ganglion damage have not been defined. We obtained rare material consisting of seven sensory ganglia from three donors who had suffered from herpes zoster between 1 and 4.5 months before death but who had not died from herpes zoster. We performed immunostaining to investigate the site of VZV infection and to phenotype immune cells in these ganglia. VZV antigen was localized almost exclusively to neurons, and in at least one case it persisted long after resolution of the rash. The large immune infiltrate consisted of noncytolytic CD8؉ T cells, with lesser numbers of CD4 ؉ T cells, B cells, NK cells, and macrophages and no dendritic cells. VZV antigen-positive neurons did not express detectable major histocompatibility complex (MHC) class I, nor did CD8 ؉ T cells surround infected neurons, suggesting that mechanisms of immune control may not be dependent on direct contact. This is the first report defining the nature of the immune response in ganglia following herpes zoster and provides evidence for persistence of non-latency-associated viral antigen and inflammation beyond rash resolution.Varicella-zoster virus (VZV) is a highly species-specific human alphaherpesvirus that infects a majority of the world's population. VZV causes two clinically significant diseases; varicella (chicken pox) and herpes zoster (shingles) (5,8,19). Varicella is characterized by widespread cutaneous vesicular lesions and is a consequence of primary VZV infection in VZV-naïve individuals. While varicella is a relatively mild disease in immunocompetent children, it can cause significant morbidity in healthy adults and is frequently life threatening in immunocompromised individuals (3,4,22). The innate and adaptive immune responses act to eliminate replicating virus during varicella, but not all virus is cleared during this time, with some presumed to access nerve axons in the skin, enabling transport to neurons in sensory ganglia, where the virus is able to establish a lifelong latent infection (5,8,12,13,20,32). An alternative possibility is that virus is transported to ganglia via hematogenous spread (36). The ability of VZV to establish latency in the host is critical to the success of this virus as a human pathogen.VZV reactivation from latency (herpes zoster) causes serious disease in older and immunocompromised individuals and is characterized by vesicular skin rash in a dermatomal distribution with preceding and concomitant pain (7,10,21,68). During reactivation, sensory ganglia are sites of viral replication, where an intense inflammatory response is induced and widespread necrosis of glial cells and neur...

“…As complex as the analysis of HSV latency in human ganglia has been, studies of the cellular distribution of latent VZV DNA in human ganglia have been even more so, despite numerous attempts using ISH (12,21,25,27,31), in situ PCR (17,27), immunohistochemical staining (8,26,32,36), and PCR of dissociated ganglion cells (28,30). There had long remained controversy, for example, as to which cells primarily harbor latent VZV.…”

mentioning

confidence: 99%

Laser-Capture Microdissection: Refining Estimates of the Quantity and Distribution of Latent Herpes Simplex Virus 1 and Varicella-Zoster Virus DNA in Human Trigeminal Ganglia at the Single-Cell Level

Wang

Lau

Morales

et al. 2005

133

105

Herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) establish lifelong latent infections in human sensory ganglia, processes that have been investigated extensively but are still not fully elucidated. It is well established that during latency, infectious HSV-1 and VZV particles are not produced (40,41,56), but small subsets of their genes are expressed (11,12,13,21,25,27,31,35,44,52). These latent viruses, however, are subject to single or multiple rounds of reactivation and can result in recrudescent disease (7, 59). For HSV, gene expression in latency is extremely restricted in that only the latency-associated transcripts (LAT) accumulate to levels high enough to be detected by in situ hybridization (ISH) (4,11,13,44,49,50,52). Although there is no confirmation that LAT encodes a protein that regulates HSV latency and reactivation, it has been documented that the 5Ј portion of the LAT gene facilitates the efficient establishment and reactivation from latency in experimentally infected animals (3,10,16,23,38,48,54,55).The discovery and detection of LAT by ISH enabled an indirect estimate of the percentages of animal and human sensory ganglion neurons that are latently infected. ISH studies in our laboratory, for example, showed that LAT can be detected in 0.2 to 4.3% of the neurons in human trigeminal ganglia (TG) (11), a range similar to that reported for experimentally infected mice, rabbits, and guinea pigs (4,22,44). Because the in situ detection of LAT is merely a surrogate marker for HSV latency, it is possible that many more neurons are latently infected but their LAT expression or accumulation is too low to be detected by this technique. In accord with this possibility, a variety of tools have been used to better estimate the numbers of HSV-1 DNA-containing neurons in experimental animals, including in situ PCR (27,33,34,42,43), contextual analysis (45, 47), and laser-capture microdissection (LCM) (6). These studies revealed that, in mice and rats, neurons that are LAT positive by ISH represent but a fraction of those harboring HSV-1 DNA (6,33,42,45).In the past several years, using real-time DNA PCR assays, the latent HSV-1 DNA load in human TG was estimated to be hundreds to thousands of copies/g of total ganglion DNA (9, 39), suggesting that a higher proportion of cells might be latently infected than are identified by ISH. The actual percentages of neurons that harbor latent HSV-1 DNA and the ranges of viral genome copy numbers in individual neurons, however, were addressed more directly only recently by PCR of dissociated human TG cells (5).As complex as the analysis of HSV latency in human ganglia has been, studies of the cellular distribution of latent VZV DNA in human ganglia have been even more so, despite numerous attempts using ISH (12,21,25,27,31), in situ PCR (17, 27), immunohistochemical staining (8, 26, 32, 36), and PCR of dissociated ganglion cells (28, 30). There had long remained controversy, for example, as to which cells primarily harbor latent VZV. Our laboratory r...