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T-Cell tropism of simian varicella virus during primary infection.

Ouwendijk WJ, Mahalingam R, de Swart RL, Haagmans BL, van Amerongen G, Getu S, Gilden D, Osterhaus AD, Verjans GM - PLoS Pathog. (2013)

Bottom Line: Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt.In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons.In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

View Article: PubMed Central - PubMed

Affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.

ABSTRACT
Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

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Schematic presentation of primary SVV infection.Figure shows the kinetics of SVV infection and virus-infected cell types in African green monkeys during primary SVV infection. Horizontal lines indicate the time-frame covered by the sampling days. Width of the black bars indicates onset and severity of clinical signs, amount of SVV DNA detected in blood and the sampled organs, and the frequency of SVV-infected cells in peripheral blood during primary SVV infection. Note that BAL samples were obtained no earlier than 5 dpi and animals were euthanized no earlier than 9 dpi. BAL: bronchoalveolar lavage; NK cells: natural killer cells; DC: dendritic cell; TCM: central memory T-cells; TEM: effector memory T-cells.
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ppat-1003368-g008: Schematic presentation of primary SVV infection.Figure shows the kinetics of SVV infection and virus-infected cell types in African green monkeys during primary SVV infection. Horizontal lines indicate the time-frame covered by the sampling days. Width of the black bars indicates onset and severity of clinical signs, amount of SVV DNA detected in blood and the sampled organs, and the frequency of SVV-infected cells in peripheral blood during primary SVV infection. Note that BAL samples were obtained no earlier than 5 dpi and animals were euthanized no earlier than 9 dpi. BAL: bronchoalveolar lavage; NK cells: natural killer cells; DC: dendritic cell; TCM: central memory T-cells; TEM: effector memory T-cells.

Mentions: The current study is the first to present experimental evidence (summarized in Fig. 8) that supports the role of memory T-cells in the inter-organ dissemination of varicella virus in its natural and immunocompetent host. Our current hypothesis on the pathogenesis of primary SVV infection is presented in Figure 9. We hypothesize that upon intratracheal inoculation, SVV replicates in the respiratory tract and infects epithelial cells, alveolar myeloid cells (AM and/or DC) and T-cells in the lungs. Subsequently, the virus enters the circulation as cell-associated virus predominantly within memory T-cells, first within CM and subsequently within EM T-cells. Most likely, virus-infected alveolar myeloid cells transport SVV to lung-draining lymph nodes, with subsequent transfer of SVV to memory T-cells. Peak viremia coincided with onset of fever and appearance of skin rash. SVV reached the skin by the hematogenous route, most likely via virus-infected memory T-cells. SVV may enter ganglia by retrograde axonal transport from the infected epithelia and/or by the hematogenous route. In addition to memory T-cells, other lymphocyte subsets may also contribute to the viremic spread of SVV. Virus-infected DC, NK cells, B-cells and monocytes were detected in peripheral blood at 5 dpi, albeit at low frequencies compared to memory T-cells. The contribution of each lymphocyte population in transfer of SVV to its target organs will be addressed in future studies by analyzing virus-infected lymphocytes in tissues of animals euthanized during peak viremia at 5–7 dpi.


T-Cell tropism of simian varicella virus during primary infection.

Ouwendijk WJ, Mahalingam R, de Swart RL, Haagmans BL, van Amerongen G, Getu S, Gilden D, Osterhaus AD, Verjans GM - PLoS Pathog. (2013)

Schematic presentation of primary SVV infection.Figure shows the kinetics of SVV infection and virus-infected cell types in African green monkeys during primary SVV infection. Horizontal lines indicate the time-frame covered by the sampling days. Width of the black bars indicates onset and severity of clinical signs, amount of SVV DNA detected in blood and the sampled organs, and the frequency of SVV-infected cells in peripheral blood during primary SVV infection. Note that BAL samples were obtained no earlier than 5 dpi and animals were euthanized no earlier than 9 dpi. BAL: bronchoalveolar lavage; NK cells: natural killer cells; DC: dendritic cell; TCM: central memory T-cells; TEM: effector memory T-cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649965&req=5

ppat-1003368-g008: Schematic presentation of primary SVV infection.Figure shows the kinetics of SVV infection and virus-infected cell types in African green monkeys during primary SVV infection. Horizontal lines indicate the time-frame covered by the sampling days. Width of the black bars indicates onset and severity of clinical signs, amount of SVV DNA detected in blood and the sampled organs, and the frequency of SVV-infected cells in peripheral blood during primary SVV infection. Note that BAL samples were obtained no earlier than 5 dpi and animals were euthanized no earlier than 9 dpi. BAL: bronchoalveolar lavage; NK cells: natural killer cells; DC: dendritic cell; TCM: central memory T-cells; TEM: effector memory T-cells.
Mentions: The current study is the first to present experimental evidence (summarized in Fig. 8) that supports the role of memory T-cells in the inter-organ dissemination of varicella virus in its natural and immunocompetent host. Our current hypothesis on the pathogenesis of primary SVV infection is presented in Figure 9. We hypothesize that upon intratracheal inoculation, SVV replicates in the respiratory tract and infects epithelial cells, alveolar myeloid cells (AM and/or DC) and T-cells in the lungs. Subsequently, the virus enters the circulation as cell-associated virus predominantly within memory T-cells, first within CM and subsequently within EM T-cells. Most likely, virus-infected alveolar myeloid cells transport SVV to lung-draining lymph nodes, with subsequent transfer of SVV to memory T-cells. Peak viremia coincided with onset of fever and appearance of skin rash. SVV reached the skin by the hematogenous route, most likely via virus-infected memory T-cells. SVV may enter ganglia by retrograde axonal transport from the infected epithelia and/or by the hematogenous route. In addition to memory T-cells, other lymphocyte subsets may also contribute to the viremic spread of SVV. Virus-infected DC, NK cells, B-cells and monocytes were detected in peripheral blood at 5 dpi, albeit at low frequencies compared to memory T-cells. The contribution of each lymphocyte population in transfer of SVV to its target organs will be addressed in future studies by analyzing virus-infected lymphocytes in tissues of animals euthanized during peak viremia at 5–7 dpi.

Bottom Line: Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt.In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons.In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

View Article: PubMed Central - PubMed

Affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.

ABSTRACT
Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

Show MeSH
Related in: MedlinePlus