Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice

Moffat, Jennifer F.; Stein, Marshall D.; Kaneshima, Hideto; Arvin, Ann M.

doi:10.1128/jvi.69.9.5236-5242.1995

Cited by 224 publications

(91 citation statements)

References 26 publications

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“…Although many studies have demonstrated a role for T cells in varicella pathogenesis (Moffat et al, 1995;Ku et al, 2002;Ouwendijk et al, 2013;Schaap et al, 2005), the impact of VZV infection on T cell function remains poorly understood due to limited access to T cells infected in vivo. In this study, we leveraged a robust animal model where rhesus macaques are intrabronchially infected with the closely related SVV to address this question.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that T cells are highly susceptible to VZV infection and may play a critical role in its dissemination to the skin and ganglia. Specifically, direct inoculation of fetal thymus/liver implanted under the kidney capsule of SCID-hu mice with VZV-infected fibroblasts results in the infection of CD4+ and CD8+ thymocytes (Moffat et al, 1995). In addition, in vitro experiments have shown that VZV has a high propensity to infect tonsillar T cells (Ku et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Simian varicella virus causes robust transcriptional changes in T cells that support viral replication

Arnold

Messaoudi

2017

Virus Research

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Varicella zoster virus (VZV) causes varicella (chickenpox) during acute infection. Several studies have shown that T cells are early and preferential targets of VZV infection that play a critical role in disseminating VZV in to the skin and ganglia. However, the transcriptional changes that occur in VZV-infected T cells remain unclear due to limited access to clinical samples and robust translational animal models. In this study, we used a nonhuman primate model of VZV infection where rhesus macaques are infected with the closely related Simian Varicella Virus (SVV) to provide novel insights into VZV-T cell interactions. RNA sequencing of bronchial alveolar lavage-resident T cells isolated from infected rhesus macaques show that SVV infection alters expression of genes important for regulation of gene expression, cell cycle progression, metabolism, and antiviral immunity. These data provide insight into cellular processes that may support viral replication, facilitate SVV dissemination, and evade host defense.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simian varicella virus causes robust transcriptional changes in T cells that support viral replication

Arnold

Messaoudi

2017

Virus Research

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“…This suggestion is further supported by observations made in autopsy specimens obtained from vaccinated children dying suddenly of unrelated causes, that viral DNA and transcripts are found not only in ganglia innervating the vaccination site, but also bilaterally in distant ganglia ). Still to be determined, however, is whether the VZV that establishes latent infection can only be delivered to ganglia by axons that acquire VZV released as infectious particles in the skin, or whether they can also become infected by the T lymphocytes that carry VZV during a viremia (Abendroth et al 2001;Asanuma et al 2000;Koropchak et al 1989;Ku et al 2002;Moffat et al 1995;Schaap et al 2005). There is evidence that VZV-infected lymphocytes release infectious cell-free viral particles (Moffat et al 1995), although this evidence is not universally accepted and contrary data have also been reported (Soong et al 2000).…”

Section: Introductionmentioning

confidence: 99%

VZV Infection of Keratinocytes: Production of Cell-Free Infectious Virions In Vivo

Gershon

2010

Current Topics in Microbiology and Immunology

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Varicella-zoster virus (VZV) is the cause of varicella (chickenpox) and zoster (shingles). Varicella is a primary infection that spreads rapidly in epidemics while zoster is a secondary infection that occurs sporadically as a result of the reactivation of previously acquired VZV. Reactivation is made possible by the establishment of latency during the initial episode of varicella. The signature lesions of both varicella and zoster are cutaneous vesicles, which are filled with a clear fluid that is rich in infectious viral particles. It has been postulated that the skin is the critical organ in which both host-to-host transmission of VZV and the infection of neurons to establish latency occur. This hypothesis is built on evidence that the large cation-independent mannose 6-phosphate receptor (MPRci) interacts with VZV in virtually all infected cells, except those of the suprabasal epidermis, in a way that prevents the release of infectious viral particles. Specifically, the virus is diverted in an MPRci-dependent manner from the secretory pathway to late endosomes where VZV is degraded. Because nonepidermal cells are thus prevented from releasing infectious VZV, a slow process, possibly involving fusion of infected cells with their neighbors, becomes the means by which VZV is disseminated. In the epidermis, however, the maturation of keratinocytes to give rise to corneocytes in the suprabasal epidermis is associated uniquely with a downregulation of the MPRci. As a result, the diversion of VZV to late endosomes does not occur in the suprabasal epidermis where vesicular lesions occur. The formation of the waterproof, chemically resistant barrier of the epidermis, however, requires that constitutive secretion outlast the downregulation of the endosomal pathway. Infectious VZV is therefore secreted by default, accounting for the presence of infectious virions in vesicular fluid. Sloughing of corneocytes, aided by scratching, then aerosolizes the virus, which can float with dust to be inhaled by susceptible hosts. Infectious virions also bathe the terminals of those sensory neurons that innervate the epidermis. These terminals become infected with VZV and provide a route, retrograde transport, which can conduct VZV to cranial nerve (CNG), dorsal root ganglia (DRG), and enteric ganglia (EG) to establish latency. Reactivation returns VZV to the skin, now via anterograde transport in axons, to cause the lesions of zoster. Evidence in support of these hypotheses includes observations of the VZV-infected human epidermis and studies of guinea pig neurons in an in vitro model system.

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“…VZV infection of the respiratory mucosal epithelium is followed by infection of or capture by dendritic cells (DCs), which traffic to regional lymph nodes or tonsils and transfer VZV to T cells (10)(11)(12). Infected T cells then home to the skin to infect cutaneous epithelial cells, resulting in the characteristic varicella lesions (13)(14)(15). In vitro and in vivo studies using the humanized SCID mouse model have also demonstrated that tonsillar T cells are susceptible to VZV infection and can transport VZV to the skin (12,13,16).…”

mentioning

confidence: 99%

Intrabronchial Infection of Rhesus Macaques with Simian Varicella Virus Results in a Robust Immune Response in the Lungs

Haberthur

Meyer

Arnold

et al. 2014

J Virol

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Varicella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella lesions or by direct contact with infectious vesicular fluid. However, the ensuing immune response in the lungs remains incompletely understood. We have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we performed an in-depth analysis of the host immune response to acute SVV infection in the lungs and peripheral blood. We report that acute SVV infection results in a robust innate immune response in the lungs, characterized by the production of inflammatory cytokines, chemokines, and growth factors as well as an increased frequency of plasmacytoid dendritic cells (DCs) that corresponded with alpha interferon (IFN-␣) production and a rapid decrease in viral loads in the lungs. This is followed by T and B cell proliferation, antibody production, T cell differentiation, and cytokine production, which correlate with the complete cessation of viral replication. Although terminally differentiated CD8 T cells became the predominant T cell population in bronchoalveolar lavage cells, a higher percentage of CD4 T cells were SVV specific, which suggests a critical role for these cells in the resolution of primary SVV infection in the lungs. Given the homology between SVV and VZV, our data provide insight into the immune response to VZV within the lung. IMPORTANCEAlthough primary VZV infection occurs primarily via the respiratory route, the host response in the lungs and its contribution to the cessation of viral replication and establishment of latency remain poorly understood. The difficulty in accessing lung tissue and washes from individuals infected with VZV has hampered efforts to address this knowledge gap. SVV infection of rhesus macaques is an important model of VZV infection of humans; therefore, we utilized this animal model to gain a comprehensive view of the kinetics of the immune response to SVV in the lung and its relationship to the resolution of acute infection in respiratory tissues. These data not only advance our understanding of host immunity to VZV, a critical step in developing new vaccines, but also provide additional insight into immunity to respiratory pathogens. P rimary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, occurs primarily through the inhalation of virus-laden saliva droplets (1, 2) or airborne virions from varicella lesions (3) or by contact with infectious vesicular fluid (4). The incubation period of varicella can range from 10 to 21 days and usually results in a benign self-limiting disease characterized by the appearance of vesicular exanthem, fever, and malaise (5). Current evidence suggests VZV can infect and replicate within the respiratory mucosal epithelium....

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Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice

Cited by 224 publications

References 26 publications

Simian varicella virus causes robust transcriptional changes in T cells that support viral replication

Simian varicella virus causes robust transcriptional changes in T cells that support viral replication

VZV Infection of Keratinocytes: Production of Cell-Free Infectious Virions In Vivo

Intrabronchial Infection of Rhesus Macaques with Simian Varicella Virus Results in a Robust Immune Response in the Lungs

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