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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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Detection of SVV in lymphoid organs from infected African green monkeys.(A) Real-time qPCR analysis of SVV DNA load in tonsil, lymph nodes and spleen from SVV-wt− (closed squares) and SVV-EGFP− (open squares) infected monkeys at 9, 13 and 20 dpi. Squares indicate individual tissues, i.e., tonsils (red), tracheobronchial lymph nodes (LN) (green), axillary LN (pink), mandibular LN (blue), inguinal LN (orange) and spleen (black). Horizontal bar indicates the median value. (B–D) Serial sections of tonsil from an SVV-wt−infected monkey stained with hematoxylin and eosin (inset shows a Cowdry type A intranuclear inclusion body) (B) or examined immunohistochemically using rabbit anti-SVV antibodies (C) or control normal rabbit serum (D). Magnification: 200×. The area of tonsils containing multiple intranuclear inclusion bodies contained numerous cells expressing SVV protein. **p<0.01 by Mann-Whitney test.
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ppat-1003368-g005: Detection of SVV in lymphoid organs from infected African green monkeys.(A) Real-time qPCR analysis of SVV DNA load in tonsil, lymph nodes and spleen from SVV-wt− (closed squares) and SVV-EGFP− (open squares) infected monkeys at 9, 13 and 20 dpi. Squares indicate individual tissues, i.e., tonsils (red), tracheobronchial lymph nodes (LN) (green), axillary LN (pink), mandibular LN (blue), inguinal LN (orange) and spleen (black). Horizontal bar indicates the median value. (B–D) Serial sections of tonsil from an SVV-wt−infected monkey stained with hematoxylin and eosin (inset shows a Cowdry type A intranuclear inclusion body) (B) or examined immunohistochemically using rabbit anti-SVV antibodies (C) or control normal rabbit serum (D). Magnification: 200×. The area of tonsils containing multiple intranuclear inclusion bodies contained numerous cells expressing SVV protein. **p<0.01 by Mann-Whitney test.

Mentions: Alveolar macrophages and lung-resident DC transport antigens to lung-draining lymph nodes for presentation to T-cells [33], [34], and VZV-infected human DCs can transfer infectious virus to T-cells in vitro[35]. We hypothesized that SVV-infected alveolar myeloid cells transport SVV to draining lymph nodes for subsequent virus transfer to memory T-cells. High SVV DNA loads were detected in lymph nodes, tonsils and spleens of SVV-infected monkeys at 9 dpi, declining rapidly thereafter (Fig. 5A). Cells in lymph nodes and tonsils of SVV-infected monkeys contained intranuclear inclusions bodies and SVV antigen (Fig. 5B and C). Tracheobronchial lymph nodes showed more pronounced SVV-induced histopathology compared to peripheral lymph nodes (data not shown). However, SVV DNA loads were comparable in different lymph nodes collected at 9 dpi (Fig. 5A), emphasizing the need to investigate lymph nodes at earlier times after infection. In addition, detection of SVV-infected memory T-cells in blood may represent lung-resident T-cells involved in SVV dissemination. SVV infects alveolar epithelial cells leading to alveolar wall damage (data not shown) [19], [27], [36], which may result in egress of SVV-infected T-cells into the circulation.


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)

Detection of SVV in lymphoid organs from infected African green monkeys.(A) Real-time qPCR analysis of SVV DNA load in tonsil, lymph nodes and spleen from SVV-wt− (closed squares) and SVV-EGFP− (open squares) infected monkeys at 9, 13 and 20 dpi. Squares indicate individual tissues, i.e., tonsils (red), tracheobronchial lymph nodes (LN) (green), axillary LN (pink), mandibular LN (blue), inguinal LN (orange) and spleen (black). Horizontal bar indicates the median value. (B–D) Serial sections of tonsil from an SVV-wt−infected monkey stained with hematoxylin and eosin (inset shows a Cowdry type A intranuclear inclusion body) (B) or examined immunohistochemically using rabbit anti-SVV antibodies (C) or control normal rabbit serum (D). Magnification: 200×. The area of tonsils containing multiple intranuclear inclusion bodies contained numerous cells expressing SVV protein. **p<0.01 by Mann-Whitney test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3649965&req=5

ppat-1003368-g005: Detection of SVV in lymphoid organs from infected African green monkeys.(A) Real-time qPCR analysis of SVV DNA load in tonsil, lymph nodes and spleen from SVV-wt− (closed squares) and SVV-EGFP− (open squares) infected monkeys at 9, 13 and 20 dpi. Squares indicate individual tissues, i.e., tonsils (red), tracheobronchial lymph nodes (LN) (green), axillary LN (pink), mandibular LN (blue), inguinal LN (orange) and spleen (black). Horizontal bar indicates the median value. (B–D) Serial sections of tonsil from an SVV-wt−infected monkey stained with hematoxylin and eosin (inset shows a Cowdry type A intranuclear inclusion body) (B) or examined immunohistochemically using rabbit anti-SVV antibodies (C) or control normal rabbit serum (D). Magnification: 200×. The area of tonsils containing multiple intranuclear inclusion bodies contained numerous cells expressing SVV protein. **p<0.01 by Mann-Whitney test.
Mentions: Alveolar macrophages and lung-resident DC transport antigens to lung-draining lymph nodes for presentation to T-cells [33], [34], and VZV-infected human DCs can transfer infectious virus to T-cells in vitro[35]. We hypothesized that SVV-infected alveolar myeloid cells transport SVV to draining lymph nodes for subsequent virus transfer to memory T-cells. High SVV DNA loads were detected in lymph nodes, tonsils and spleens of SVV-infected monkeys at 9 dpi, declining rapidly thereafter (Fig. 5A). Cells in lymph nodes and tonsils of SVV-infected monkeys contained intranuclear inclusions bodies and SVV antigen (Fig. 5B and C). Tracheobronchial lymph nodes showed more pronounced SVV-induced histopathology compared to peripheral lymph nodes (data not shown). However, SVV DNA loads were comparable in different lymph nodes collected at 9 dpi (Fig. 5A), emphasizing the need to investigate lymph nodes at earlier times after infection. In addition, detection of SVV-infected memory T-cells in blood may represent lung-resident T-cells involved in SVV dissemination. SVV infects alveolar epithelial cells leading to alveolar wall damage (data not shown) [19], [27], [36], which may result in egress of SVV-infected T-cells into the circulation.

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