权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Marta Maria Gaglia
金额：
$ 37.76万
依托单位：
TUFTS UNIVERSITY BOSTON
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

来源：
https://reporter.nih.gov/project-details/10403006
关键词：
AIDS related cancer Acquired Immunodeficiency Syndrome Affect Africa South of the Sahara Antiviral Response Apoptosis Apoptotic Autoimmune Diseases Biology CASP8 gene Caspase Cell Death Cells Cessation of life Communicable Diseases Complex DNA Data Development Disease Enzymes Genetic Transcription Herpesviridae Infections Human Herpesvirus 8 Immune Evasion Immune response Infection Innate Immune Response Interferon Type I Interferons Kaposi Sarcoma Lead Lytic Phase Maintenance Mediating Mediator of activation protein Molecular Nature Oncogenic Viruses Pathway interactions Peptide Hydrolases Play Production Proteins Receptor Signaling Regulation Regulatory Pathway Reporting Role Signal Transduction Stimulus TLR3 gene Testing Toll-Like Receptor Pathway Toll-like receptors Tumor Immunity Up-Regulation Viral Virus Virus Replication Work cancer type druggable target experience inhibitor insight mutant new therapeutic target overexpression pathogen prevent reactivation from latency receptor response targeted treatment tumor virus host interaction

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