Determining how Kaposi's sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses

确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应

基本信息

  • 批准号:
    10403006
  • 负责人:
  • 金额:
    $ 37.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-01 至 2022-09-30
  • 项目状态:
    已结题

项目摘要

Project summary. During lytic infection, the AIDS-associated tumor virus Kaposi’s sarcoma-associated herpesvirus (KSHV) blocks cells from activating the anti-viral type I interferon (IFN) responses. This block of the innate immune response facilitates efficient viral replication, which in turn contributes to development of Kaposi’s sarcoma. Thus, elucidating the mechanisms by which KSHV evades the host innate immune response may provide insights on how to target this and other KSHV-induced tumors. However, because of the complex and redundant nature of the type I IFN induction pathway, how KSHV blocks this early antiviral response is still incompletely understood. In a previous study, we found that the host protease caspase-8 is a major mediator of type I IFN inhibition by KSHV. KSHV reactivation from latency only triggers minimal type I IFN induction, but there is a much stronger transcriptional induction and secretion of type I IFNs when caspase-8 is also inhibited. This stronger IFN induction, in turn, reduces KSHV reactivation. These results indicate that caspase-8 activity is necessary to inhibit IFN induction, and thus promotes KSHV replication. This finding was surprising because caspase-8 activation is generally considered antiviral as it induces apoptotic cell death. However, we do not detect wide-spread cell death during reactivation from latency despite caspase-8 activation, suggesting that caspase-8 is hijacked and repurposed by KSHV to inhibit type I IFN responses. At present, the molecular mechanisms that lead to caspase-8 activity and the pathways that are targeted by caspase-8 to control type I IFN during KSHV infection remain unclear. We have new preliminary data suggesting that caspase-8 is activated by a pathogen sensing pathway, the Toll-like receptor (TLR) pathway, as a cellular response to infection. Caspase-8 then proceeds to inhibit a different pathogen sensing pathway, cGAS-mediated DNA sensing. Therefore, we hypothesize that KSHV is taking advantage of a TLR-mediated cellular response to infection that activates caspase-8. KSHV is then able to redirect this activity to inhibit DNA sensing instead of activating apoptosis. We will test this hypothesis and determine how caspase-8 is activated by TLR signaling in KSHV-infected cells without triggering cell death (Aim 1), and which host protein(s) are cleaved by caspase-8 to block cGAS-induced type I IFN responses (Aim 2). Moreover, we will also investigate whether and how caspase activity is connected to other previously described mechanisms of immune evasion by KSHV (Aim 3). As caspase-8 is a druggable target, understanding how caspase-8 is used by KSHV to regulate type I IFNs and promote its replication will reveal whether and how this enzyme could be exploited for KSHV therapy. This is important as there are no target therapies for this virus, and Kaposi’s sarcoma remains one of the leading types of cancers in sub-Saharan Africa and the second most common AIDS-associated malignancy in the US. This project will also uncover fundamental aspects of caspase signaling that may play a role in other diseases connected to IFN.
项目总结。在溶性感染期间,艾滋病相关肿瘤病毒与卡波西氏肉瘤相关

项目成果

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科研奖励数量(0)
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Marta Maria Gaglia其他文献

Marta Maria Gaglia的其他文献

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{{ truncateString('Marta Maria Gaglia', 18)}}的其他基金

Determining how Kaposi’s sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses
确定卡波西肉瘤相关疱疹病毒如何劫持半胱天冬酶功能以抑制抗病毒反应
  • 批准号:
    10729751
  • 财政年份:
    2021
  • 资助金额:
    $ 37.76万
  • 项目类别:
Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein
流感 PA-X 宿主关闭蛋白的分子机制
  • 批准号:
    9913984
  • 财政年份:
    2018
  • 资助金额:
    $ 37.76万
  • 项目类别:
Molecular Mechanism of Action of the Influenza PA-X Host Shutoff Protein
流感 PA-X 宿主关闭蛋白的分子机制
  • 批准号:
    10381706
  • 财政年份:
    2018
  • 资助金额:
    $ 37.76万
  • 项目类别:

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