Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>

ABSTRACT A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can...

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Autores principales:	Sandeep Steven Reddy, Hui-Chen Chang Foreman, Thubten Ozula Sioux, Gee Ho Park, Valeria Poli, Nancy C. Reich, Laurie T. Krug
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c5c7f8dfc23c4a168d2deefe4cb298fa
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spelling	oai:doaj.org-article:c5c7f8dfc23c4a168d2deefe4cb298fa2021-11-15T15:50:18ZAblation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>10.1128/mBio.00723-162150-7511https://doaj.org/article/c5c7f8dfc23c4a168d2deefe4cb298fa2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00723-16https://doaj.org/toc/2150-7511ABSTRACT A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. Many cancers, including those associated with members of the gammaherpesvirus family, Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus, express elevated levels of active host signal transducer and activator of transcription-3 (STAT3). STAT3 is activated by tyrosine phosphorylation in response to many cytokines and can orchestrate effector responses that include proliferation, inflammation, metastasis, and developmental programming. However, the contribution of STAT3 to gammaherpesvirus pathogenesis remains to be completely understood. This is the first study to have identified STAT3 as a critical host determinant of the ability of gammaherpesvirus to establish long-term latency in an animal model of disease. Following an acute infection, murine gammaherpesvirus 68 (MHV68) established latency in resident B cells, but establishment of latency was dramatically reduced in animals with a B cell-specific STAT3 deletion. The lack of STAT3 in B cells did not impair germinal center responses for immunoglobulin (Ig) class switching in the spleen and did not reduce either total or virus-specific IgG titers. Although ablation of STAT3 in B cells did not have a global effect on these assays of B cell function, it had long-term consequences for the viral load of the host, since virus latency was reduced at 6 to 8 weeks postinfection. Our findings establish host STAT3 as a mediator of gammaherpesvirus persistence. IMPORTANCE The insidious ability of gammaherpesviruses to establish latent infections can have detrimental consequences for the host. Identification of host factors that promote viral latency is essential for understanding latency mechanisms and for therapeutic interventions. We provide the first evidence that STAT3 expression is needed for murine gammaherpesvirus 68 to establish latency in primary B cells during an active immune response to infection. STAT3 deletion in B cells does not impair adaptive immune control of the virus, but loss of STAT3 in B cells has a long-lasting impact on viral persistence. These results indicate a potential therapeutic benefit of STAT3 inhibitors for combating gammaherpesvirus latency and, thereby, associated pathologies.Sandeep Steven ReddyHui-Chen Chang ForemanThubten Ozula SiouxGee Ho ParkValeria PoliNancy C. ReichLaurie T. KrugAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sandeep Steven Reddy Hui-Chen Chang Foreman Thubten Ozula Sioux Gee Ho Park Valeria Poli Nancy C. Reich Laurie T. Krug Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
description	ABSTRACT A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. Many cancers, including those associated with members of the gammaherpesvirus family, Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus, express elevated levels of active host signal transducer and activator of transcription-3 (STAT3). STAT3 is activated by tyrosine phosphorylation in response to many cytokines and can orchestrate effector responses that include proliferation, inflammation, metastasis, and developmental programming. However, the contribution of STAT3 to gammaherpesvirus pathogenesis remains to be completely understood. This is the first study to have identified STAT3 as a critical host determinant of the ability of gammaherpesvirus to establish long-term latency in an animal model of disease. Following an acute infection, murine gammaherpesvirus 68 (MHV68) established latency in resident B cells, but establishment of latency was dramatically reduced in animals with a B cell-specific STAT3 deletion. The lack of STAT3 in B cells did not impair germinal center responses for immunoglobulin (Ig) class switching in the spleen and did not reduce either total or virus-specific IgG titers. Although ablation of STAT3 in B cells did not have a global effect on these assays of B cell function, it had long-term consequences for the viral load of the host, since virus latency was reduced at 6 to 8 weeks postinfection. Our findings establish host STAT3 as a mediator of gammaherpesvirus persistence. IMPORTANCE The insidious ability of gammaherpesviruses to establish latent infections can have detrimental consequences for the host. Identification of host factors that promote viral latency is essential for understanding latency mechanisms and for therapeutic interventions. We provide the first evidence that STAT3 expression is needed for murine gammaherpesvirus 68 to establish latency in primary B cells during an active immune response to infection. STAT3 deletion in B cells does not impair adaptive immune control of the virus, but loss of STAT3 in B cells has a long-lasting impact on viral persistence. These results indicate a potential therapeutic benefit of STAT3 inhibitors for combating gammaherpesvirus latency and, thereby, associated pathologies.
format	article
author	Sandeep Steven Reddy Hui-Chen Chang Foreman Thubten Ozula Sioux Gee Ho Park Valeria Poli Nancy C. Reich Laurie T. Krug
author_facet	Sandeep Steven Reddy Hui-Chen Chang Foreman Thubten Ozula Sioux Gee Ho Park Valeria Poli Nancy C. Reich Laurie T. Krug
author_sort	Sandeep Steven Reddy
title	Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
title_short	Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
title_full	Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
title_fullStr	Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
title_full_unstemmed	Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>
title_sort	ablation of stat3 in the b cell compartment restricts gammaherpesvirus latency <italic toggle="yes">in vivo</italic>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/c5c7f8dfc23c4a168d2deefe4cb298fa
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Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency <italic toggle="yes">In Vivo</italic>

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