Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection


KSHV infection of endothelial cells in vivo causes Kaposi's sarcoma and understanding the steps involved in de novo KSHV infection of these cells and the consequences is important to develop therapies to counter KSHV pathogenesis. Infection of endothelial cells in vitro is preceded by the induction of a network of host signaling agents that are necessary for virus entry, gene expression and establishment of latency. Our previous studies have implicated reactive oxygen species (ROS) as part of this network. In the current study, we show that ROS activate Nrf2, a master transcriptional regulator of genes involved in ROS homeostasis, apoptosis, glucose metabolism and angiogenesis. Besides ROS, KSHV utilizes additional aspects of host signaling to induce Nrf2 activity. We also observed that infection of endothelial cells deficient in Nrf2 resulted in downregulation of multiple genes important in KSHV pathogenesis, such as COX-2 and VEGF, and affected proper expression of two hallmark KSHV genes, lytic ORF50 and latent ORF73. Taken together, this study is the first to demonstrate the importance of Nrf2 during de novo KSHV infection of endothelial cells, and establishes Nrf2 as an attractive therapeutic target to control KSHV infection, establishment of latency and the associated cancers.


Vyšlo v časopise: Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004460
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004460

Souhrn

KSHV infection of endothelial cells in vivo causes Kaposi's sarcoma and understanding the steps involved in de novo KSHV infection of these cells and the consequences is important to develop therapies to counter KSHV pathogenesis. Infection of endothelial cells in vitro is preceded by the induction of a network of host signaling agents that are necessary for virus entry, gene expression and establishment of latency. Our previous studies have implicated reactive oxygen species (ROS) as part of this network. In the current study, we show that ROS activate Nrf2, a master transcriptional regulator of genes involved in ROS homeostasis, apoptosis, glucose metabolism and angiogenesis. Besides ROS, KSHV utilizes additional aspects of host signaling to induce Nrf2 activity. We also observed that infection of endothelial cells deficient in Nrf2 resulted in downregulation of multiple genes important in KSHV pathogenesis, such as COX-2 and VEGF, and affected proper expression of two hallmark KSHV genes, lytic ORF50 and latent ORF73. Taken together, this study is the first to demonstrate the importance of Nrf2 during de novo KSHV infection of endothelial cells, and establishes Nrf2 as an attractive therapeutic target to control KSHV infection, establishment of latency and the associated cancers.


Zdroje

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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PLOS Pathogens


2014 Číslo 10
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Eozinofilní granulomatóza s polyangiitidou
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Autori: doc. MUDr. Martina Doubková, Ph.D.

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