INTRODUCTION: In Part I we presented background on the involvement of varicella zoster virus (VZV) with the enteric nervous system (ENS). That included evidence that reactivation of VZV within the ENS can infect gastrointestinal (GI) targets and cause enteric zoster.

DISCUSSION: Zhou et al.1, present a review detailing the involvement of VZV with the enteric nervous system. The reactivation of VZV with no apparent shingles on the skin surface is called zoster sine herpete (ZSH-Lewis2). ZSH is one of the atypical clinical manifestations of herpes zoster (HZ), which stems from infection and reactivation of (VZV) in the cranial nerve, spinal nerve, viscera, or autonomic nerve. In the US, there are almost one million cases of HZ each year. However, ZSH is likely to be missed or misdiagnosed, and patients may not receive timely antiviral treatment. Even with the high case rates of ZH, there is presently little epidemic data regarding ZSH. Considering that more than 95% of young adults in North American and Europe are positive for VZV, the incidence of both HZ and ZSH is expected to increase as the population ages. And in the case of ZSH, it is likely that this type of reactivation will continue to be under-reported and underrated. In 1958, Lewis2, proposed several observations pointing towards ZSH, based on the type and locations of specific pains.  The pain can be a deep boring/twisting pain arising in muscles, joints, etc., which is called “sclerotome pain”; or a superficial, burning pain in or near the called “dermatomal pain”. The pain from ZSH has been reported to be more serious, than the pain associated with HZ. Unexplained abdominal pain may be related to ZSH because salivary VZV DNA was detected in 6/11 patients of this type, 11/16 patients with zoster or varicella, and 2/2 ZSH patients. However, healthy controls (n=20) and patients with unrelated gastrointestinal disorders (n=8) were all negative for VZV DNA detection (Gershon et al3). These results indicate that ZSH may be the reason for the abdominal pain. Patients with mucosal lesions in the larynx, with sore throat, dysphagia, and hoarseness were VZV DNA positive after detecting exudates from the pharyngeal mucosal lesions. Patients in these studies all responded to, and benefited from, herpes virus antiviral therapy. Studies indicate that at the beginning of ZSH, detection of VZV DNA is more sensitive than anti-VZV antibodies, which show up later in the ZSH reactivation (Furuta et al4).

CONCLUSION: ZSH is a special form of VZV reactivation which often leads to misdiagnosis due to the lack of typical clinical manifestations. ZSH should be considered in patients with unilateral, single-root neuralgia and diagnosed with VZV DNA and/or anti-VZV IgG/IgM. Accurate diagnosis methods, timely antiviral therapy, and more ZSH related studies and guidelines will be beneficial for ZSH diagnosis and treatment.

REFERENCES:

  1. Zhou, J., J. Li, L. Ma, and S. Cao. (2020). Zoster sine herpete: a review. Korean J Pain 33(3):208-215. https://doi.org/20.3344/kjp.2020.33.3.208
  2. Lewis, GW. (1958). Zoster sine herpete. Br. Med J 2(5093):418-21. https://doi.org/10.1136/bmj.2.5093.418
  3. Gershon, A.A., J. Chen, and M.D. Gershon. (2015). Use of saliva to identify varicella zoster virus infection of the gut. Clin Infect Dis 61(4):536-44. https://doi.org/10.1093/cid/civ320.
  4. Furuta Y., S. Fukuda, S. Suzuki, T. Takasu, Y. Inuyama, and K. Nagashima. (1997). Detection of varicella-zoster virus DNA in patients with acute peripheral facial palsy by the polymerase chain reaction, and it’s use for early diagnosis of zoster sine herpete. J Med Virol 52:316-9. https://doi.org/10.1002/(SICI)1096-9071(199707)52:3<316::AID-JMV13>3.0.CO;2-G

MKTG 1071  Rev A   CO-336

INTRODUCTION: It is well known that varicella zoster virus (VZV) infects and becomes latent in neurons in ganglia of the cranial nerves and dorsal roots and upon reactivation leads to zoster (shingles). However, there are also ganglia associated with the enteric nervous system (ENS). Reactivation of VZV within the ENS can infect gastrointestinal (GI) targets and cause enteric zoster.

 

DISCUSSION: Before the reactivation of VZV in the ENS was known, varicella zoster virus was associated with inflammatory bowel disease and perforated ulcers. Enteric zoster from reactivation of vaccine-type virus (vOka) has been found to cause perforating gastric ulcers. Because the neurons in the ENS convey active VZV to visceral and vascular targets, reactivation of VZV in autonomic neurons may cause serious disease of the vasculature, or viscera, without cutaneous manifestations. Gershon & Gershon describe the mechanism of VZV latency in the ENS1. They examined isolated guinea pig enteric neurons and detected late viral proteins, glycoproteins gE, gI, and gB, as well as immediate early proteins, including ORFs 29p, 62p and 63p which were all intranuclear. Evidence of reactivation included expression of late proteins, nuclear translocation of immunofluorescence of the immediate early proteins, production of electron microscopically visible virions, transmission of infection to co-cultured MeWo cells, and death of the neurons within 72 hours of the expression of ORF61. The burden of VZV-induced GI disease cannot yet be assessed, the researchers’ observations made using salivary VZV DNA as a noninvasive marker suggest that enteric zoster may be far more common than realized. They developed a guinea pig model of VZV latency and reactivation to learn how VZV establishes and maintains latency in enteric neurons, what provokes reactivation, and the manifestations of enteric zoster. Their observations suggest that immunosuppression, combined with corticotrophin releasing hormone, induces VZV to reactivate in guinea pigs. The resulting syndrome resembled disseminated zoster. The intravenous injection of VZVORF66.GFP-infected lymphocytes produced a latent infection in almost all dorsal root ganglia and enteric neurons. This was the first animal in which latent infection and reactivation of VZV was shown. Since then, simian varicella virus has also been found to establish latency in the monkey ENS (Ouwendijk et al2). The observation that VZV-infected CD3+ lymphocytes of guinea pigs and humans transmit latent infection to enteric neurons is significant.

 

CONCLUSION: The biological reason of how lymphocytes deliver only latent VZV to neurons, including those of the ENS, is unknown. Small reactivations of VZV in the bowel might be controllable because the gut is a major immune organ and might even help to maintain long-term immunity to varicella (postulated by Gershon&Gershon), however larger reactivation events can be devastating when is causes pseudoobstrution or perforating ulcers. The hidden nature of enteric zoster and its low index of suspicion have limited what is currently known about it. Their observations with salivary VZV DNA as a noninvasive marker suggest that enteric zoster may also be a common problem. The relationship of VZV and the recurrent zoster to those who have Crohn’s disease also merits further investigation. The guinea pig model of VZV latency and reactivation described here may help to determine how VZV establishes latency in the ENS, what provokes reactivation, the manifestations of enteric zoster, and ultimately, it’s contribution to GI disease.

 

REFERENCES:

 

  1. Gershon, M. and A. Gershon. (2018). Varicella-Zoster Virus and the Enteric Nervous System. J. Inf. Dis (suppl2). 218, S113. Https://doi.org/10.1093/infdis/jiy407
  2. Ouwendijk, W.J.D., van Veen S., Mehraban, T., Mahalingam R., Verjans G. M. (2018). Simian varicella virus infects enteric neurons and α4β7 integrin-expressing gut-tropic T-cells in nonhuman primates. Viruses 10(4) 156. https://doi.org/10.3390/v10040156

MKTG 1070 – Rev A 041322

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). This short report is the conclusion of  three part series, based on the article by Kennedy et al.1 The possible role which autophagy plays in viral latency will be discussed.

DISCUSSION: Autophagy is a mechanism which host cells use to defend against viral infection. This is achieved using double-membrane vesicles, termed autophagosomes, which deliver trapped viruses to the lysosome for degradation. Specifically, autophagy initiates an innate immune response by cooperating with pattern recognition receptor signaling to induce interferon production. It also selectively degrades immune components associated with viral particles. Following degradation, autophagy coordinates adaptive immunity by delivering virus-derived antigens for presentation to T lymphocytes. The majority of VZV disease manifestations involve increased susceptibility to both primary disseminated infection and reactivation, with the latter case causing herpes zoster or CNS involvement in the form of meningitis, encephalitis and vasculitis. In vitro studies have demonstrated both pro- and antiviral evidence of interactions between VZV replication and autophagy pathways during lytic infection and shown that these virus-host interactions take place in a highly cell-type dependent manner. Whereas autophagy seems to exert antiviral roles in some contexts, the virus may also directly utilize autophagy molecules for its own benefit to enhance replication and viral egress (related to the endoplasmic reticulum and other cells organelles) and thus evade autophagy and subvert this process (Carpenter et al.2; Buckingham et al3). The finding that VZV directly inhibits autophagosome-lysosome fusion may suggest that autophagy does indeed play an important antiviral role in VZV infection, thus explaining/justifying the evolutionary adaptation of the virus to subvert autophagy processes (Graybill et al.4).

CONCLUSION: Specific knowledge concerning a possible role of autophagy in maintaining VZV latency in sensory ganglia in humans is lacking. Additional studies are needed to resolve the specific role of autophagy in VZV infection and to define to what extent altered homeostasis and autophagy processes may influence VZV reactivation and disease. It is unlikely that viral latency can be completely prevented, but current research is more likely to lead to therapies that may treat or prevent viral reactivation in both immunocompetent and immunocompromised individuals.

 

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018.
  • Carpenter, J.E., W. Jackson, L. Benetti, and C. Grose. (2011). Autophagosome formation during varicella-zoster virus infection following endoplasmic reticulum stress and the unfolded protein response. J. Virol 85, 9414-9424. https://doi.org/10.1128/JVI.00281-11.
  • Buckingham, E.M., J.E. Caprenter, W. Jackson, L. Zerboni, A.M. Arvin, and C. Grose. (2015). Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection. Proc. Natl. Acad. Sci. 112, 256-261. https://doi.org/10.1073/pnas.1417878112.
  • Graybill, C., M.J. Morgan, M.J. Levin, and K.S. Lee. (2018). Varicella-zoster virus inhibits autophagosome-lysosome fusion and the degradation stage of mTOR-mediated autophagic flux. Virology 522, 220-227. https://doi.org/10.1016/j.virol.2018.07.018.
MKTG 1068 - Rev A 021522

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). In Part I, we discussed a review by Kennedy et al1., which looked at some recent issues in Alphaherpesvirus latency, particularly in regards to VZV ganglionic latency. In Part II, we will look at the immunological aspects of Alphaherpesviruses in regards to VZV latency.

 

DISCUSSION: The use of “humanized” mouse models along with the study of human inborn errors of immunity, which results in increased susceptibility to VZV, has been of great value. The authors stated that a clear prominent role is played by cellular immunity conferred by T cells and natural killer (NK) cells. The role of humoral immunity remains less clear as a VZV infection and reactivation does not seem to be a major problem in individuals with antibody deficiencies. Previous clinical studies from the VZV pre-vaccine era did show a significant role on VZV immunoglobulins (VZIG) when given to children at risk of severe VZV infection. VZIG was prepared from donors with recent zoster and high levels of VZV specific immunoglobulins, and a small clinical study demonstrated that VZIG administration in immunosuppressed children modified rather than prevented VZV infection. This resulted in decreased morbidity of chickenpox children with leukemia. As a consequence of those findings, VZIG was widely used to protect children with cancer after exposure to varicella in the United States and Europe, from 1975-1995. Of importance, it was shown that all types of interferons (IFNs) show antiviral activity against VZV and serve essential functions in restricting VZV replication and spread, especially during the viremic phase and in the skin during varicella. IFNs were also thought to be involved in maintaining latency in sensory neuronal ganglia. Some studies suggested a greater antiviral role of Type II IFNs (IFNγ) over Type I IFNs (IFNα/β) against VZV in-vitro, while observations from patients with VZV CNS infection, pneumonitis or disseminated skin eruption/zoster in context of defective Type I or Type II IFN pathways, provided more indirect evidence of important non-redundant roles of both Type I and Type II IFNs in protecting against VZV reactivation. Despite several studies addressing these issues, the precise immune cells and immune mediators required for protective immunity in primary infection versus reactivation have not been clarified. In particular, the individual contribution from different cells types, including lymphocytes, macrophages, plasmacytoid dendritic cells and epithelial/endothelial cells, which are all present in human ganglia remains insufficiently understood and explored. In terms of the immune histological examination of ganglia from paraffin-embedded sections of ganglia obtained post-mortem from a patient with post-herpetic neuralgia years after the herpes zoster rash, revealed the presence of VZV DNA, as well as an immunological cell infiltrate composed of CD4 T cells, CD8 T cells and CD20 B cells, which provides evidence of an ongoing immunological reaction and inflammation years after the reactivation of VZV from latency, Sutherland et al2.

 

CONCLUSION: These studies, and others, lend support to the notion that some degree of chronic low-grade reactivation of Alphaherpesviruses from latency, as well as immune reactions to this event does take place over time in ganglia latently infected with VZV.

 

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018
  • Sutherland, J.P., M. Steain, M.E. Buckland, M. Rodriguez, A.L. Cunningham, B. Slobedman, and A. Abendroth. (2019) Persistence of a T Cell Infiltrate in Human Ganglia Years After Herpes Zoster and During Post-herpetic Neuralgia. Front. Microbiol. Volume 10, Article 2017. https://doi.org/10.3389/fmicb.2019.02117
MKTG 1067 - Rev A 021522

INTRODUCTION: Reactivation of varicella-zoster virus (VZV) after a primary infection (chickenpox) leads to herpes zoster (HZ-shingles). In this review by Kennedy et al1., look at some recent issues in alphaherpesvirus latency, particularly in regards to VZV ganglionic latency. The key question they ask is the nature and extent of viral gene transcription during viral latency. They look at specific viral gene transcripts and the underlying mechanisms which may be involved.

 

DISCUSSION: VZV latency is established in ganglia throughout the entire neuroaxis including the  dorsal root ganglia (DRG), trigeminal ganglia (TG) and also autonomic ganglia including the enteric ganglia. While viral reactivation may occur spontaneously, it can also follow one or more triggering factors such as diminished cell-mediated immunity to the virus as occurs with older age or immunosuppression due to drug treatment or disease, X-ray irradiation, infection, trauma or malignancy. Post-herpetic neuralgia (PHN) is the most well-known complication of HZ, causing severe and constant pain lasting longer than 3 months after the zoster rash. An early study (Cohrs et al2) used a cDNA library from the mRNA of latently infected human ganglia to show that VZV gene transcription in these ganglia was limited to VZV genes 21, 29, 62, and 63. Overall, these results identified the presence of gene 63-encoded transcripts as being the hallmark of VZV latency. However, Depledge et al3 obtained post-mortem ganglia within 6 hours of death and detected just two viral transcripts. In addition to detecting VZV ORF 63, they detected a spliced latency associated VZV transcript (VLT) that mapped antisense to the viral transactivator gene 61. This was a major finding in the VZV ganglion latency field.  These authors followed up this study by clarifying the relation of VZV ORF 63 expression to the expression of the VLT. They reported (Ouwendijk et al4) that during VZV reactivation from the latent state, broad viral gene expression was induced by the VLT-ORF 63 fusion transcript. Kennedy et al further discussed the phenotypic change in chromosomes without altering it’s DNA sequence (called epigenetic modification), particularly by the binding of histone proteins involved in postranslational modification at the 3′ C-terminal domain which forms the basis of the “histone code” that has emerged as a fundamental mechanism regulating transcription. They also discuss the immunological aspects of latency involving T cells and natural killer cells which we will cover in Part II of this report.

 

CONCLUSION: New molecular virological technologies are driving an increased interest in VZV latency. The emergence of epigenetic mechanisms and recent interest in immunological aspects of VZV latency will no doubt lead to further understanding the mechanisms of VZV latency.

REFERENCES:

  • Kennedy, P.G.E., T.H. Mogensen, and R.J. Cohrs. (2021). Recent Issues in Varicella-Zoster Virus Latency. Viruses 13, 2018. https://doi.org/10.3390/v13102018
  • Cohrs, R.J., M. Barbour, and D.H. Gilden. (1996). Varicella-zoster virus (VZV) transcription during latency in human ganglia: Detection of transcripts to genes 21, 29, 62, and 63 in a cDNA library enriched for VZV RNA. J. Virol. 70, 2789-2796. https://doi.org/10.1128/jvi.70.5.2789-2796.1996
  • Depledge, D.P., W.J.D. Ouwendijk, T. Sadaoka, S.E. Braspenning, Y. Mori, R.J. Cohrs, G.M.G.M. Verjans and J. Breuer. (2018). A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61. Nat. Communincations 9,1167. https://doi.org/10.1038/s41467-018-03569-2
  • Ouwendijk, W.J.D., D.P. Depledge, L. Rajbhandari, R. R., Lenac, S. Jonjic, J. Breuer, A. Venkatesan, G.M.G.M. Verjans, and T. Sadaoka. (2020). Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency. Nat. Communications 11,6324. https://doi.org/10.1038/s41467-020-20031-4
MKTG 1066 - Rev A 020322

INTRODUCTION: Varicella-zoster virus (VZV) is a highly contagious Herpesvirus which causes chickenpox (primary infection) or shingles (upon reactivation). VZV poses a nosocomial infection for healthcare workers and patients. The incubation period for the virus is between 10-21 days. It is generally thought that patients are infectious 1-2 days prior to rash onset and between 4-7 days post rash onset. However, there is a lack of data showing the route of transmission, other than from direct contact.

 

DISCUSSION: To better understand the route and timing of VZV transmission, Marin et al1., reviewed the medical literature to assess the routes of transmission prior to rash onset. They searched Medline, Embase, Cochrane Library and CINAHL databases for articles published (any language) through October 31 of 2019. The search terms were ‘Varicella’, ‘chickenpox’, or ‘herpes zoster’, along with ‘transmission’ or ‘spread’ or ‘epidemic’ or ‘isolation’ as well as ‘respiratory’ or ‘airborne’ or ‘nasal/pharyngeal/throat swab’ or ‘before rash’. They screened 693 articles and identified 59 for full-text review. The articles were from around the world, including Europe, Asia, and the United States. Seven articles discussed VZV transmission before varicella rash onset using epidemiological data and 10 with laboratory data. Three of these articles included data from reports of varicella cases during outbreaks in hospitals, three included institutional outbreaks (schools or one in a jail). Each report indicated transmission from an index patient who exposed contacts before being diagnosed with varicella. The reports showed that patients with varicella were infectious at various intervals before the rash appeared; <1 day before in one report, at least 1 day before in two papers, at least 2 days prior in two papers, and at least 4 days prior in one paper. Of the 10 articles that addressed VZV transmission before rash onset with laboratory evidence, five were published during 1966-1989 using the virus culture to identify virus in the oropharynx. Five articles from 1991-1999 examined evidence of VZV DNA presence in the oropharynx using polymerase chain reaction (PCR). Four studies included exposed siblings and three included exposed patients, one study included exposed daycare contacts and one included children and  adult participants in a clinical trial for acyclovir after the appearance of skin lesions. This review of literature confirms the scarcity of evidence in the medical literature on transmission of VZV before varicella rash onset. Several outbreak investigations in healthcare facilities reported potential exposure prior to rash onset in a patient with varicella but no transmission among exposed staff and patients. Laboratory evidence supporting transmission of VZV before rash onset is also very limited. VZV DNA was identified by PCR during the incubation period in only one study. However, methods for specimen collection and storage varied among the studies and may have been suboptimal. In addition, the presence of VZV DNA does not necessarily indicate infectivity or transmissible virus. Isolation of VZV in the respiratory tract of varicella patients is rarely reported. Coughing/sneezing leading to VZV transmission is not characteristic of varicella.

 

CONCLUSION: Based on the available medical literature, VZV transmission seems unlikely prior to rash onset. The authors suggest that providers should continue to implement appropriate infection control measures since the possibility of pre-rash, respiratory transmission of VZV cannot be entirely ruled out. Additional evidence using current or newly developed laboratory VZV assays would be beneficial.

 

REFERENCES:

  1. Marin, M., J. Leung, A.S. Lopez, L. Shepersky, D.S. Schmid, and A. A. Gerson. (2021). Communicability of varicella before rash onset” a literature review. Epidemiology and Infection 149, e131, 1-7. https://doi.org/10.1017/S0950268821001102
MKTG 1065 - Rev A 020322