Mechanisms of Infection by Oncogenic HPVs

致癌 HPV 感染的机制

基本信息

批准号：
10170290
负责人：
Michelle A Ozbun
金额：
$ 34.59万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170290
关键词：
ANXA2 gene Address Affect Annexins Anogenital cancer Benign Binding Biochemical Biochemical Genetics Biological Assay Cell Communication Cell Culture Techniques Cell Survival Cell membrane Cell physiology Cells Cervical Coupled Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Genetic Genetic Transcription Genital Genitalia Genome Genotype Human Human Biology Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 In Vitro Infection Infection prevention Knowledge Malignant - descriptor Malignant Neoplasms Malignant Squamous Cell Neoplasm Malignant neoplasm of anus Mammalian Cell Mediating Mediator of activation protein Membrane Microscopy Modeling Molecular Morbidity - disease rate Mucous Membrane Mus Normal Cell Oncogenic Papillomavirus Infections Pharmacology Play Predisposition Process Production Protein Inhibition Proteins Reagent Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Resolution Risk Role Science Signal Pathway Signal Transduction Skin Cancer Squamous Epithelium Surface Techniques Testing Tissues Up-Regulation Vaginal Human Papilloma Virus Video Microscopy Virion Virus Virus Diseases Woman Work Wound models base cancer cell cell growth cell type epithelial wound functional group human disease human model in vivo inhibitor/antagonist insight keratinocyte malignant oropharynx neoplasm men mouse model mutant pathogen prevent programs receptor receptor function recruit src-Family Kinases theories tool uptake vaccine access viral detection wound wound healing wound response

项目摘要

Project Summary/Abstract The epidermal growth factor receptor (EGFR) has key regulatory roles in epithelial wound healing, cell growth and cell survival in many mammalian cell types. EGFR is hijacked by many human viruses, including human papillomaviruses (HPVs), to promote their infectious entry into host cells. Yet, specific mechanisms by which EGFR activation leads to virion internalization are poorly understood. HPV types 16 and 31 interact with EGFR and the EGFR-interacting partner, the annexin A2 tetramer (A2t), at the HK plasma membrane. Our scientific premise is based on findings from our lab and from other groups: functional inhibition of EGFR or A2t proteins significantly reduces HPV entry and infection in HKs. Our CENTRAL HYPOTHESIS is that EGFR signaling promotes the translocation of A2t to the external cell membrane to initiate the infectious entry of HPV into host cells. We will define the role that EGFR and its signaling plays in promoting HPV uptake in HKs, and determine whether EGFR is directly involved in onco-HPV internalization. We will also examine how A2t cooperates with EGFR signaling to facilitate infectious entry of onco-HPV. Epithelial wounding plays an important, but poorly understood, role in papillomavirus infections in vivo. Notably, EGFR and A2t are activated in epithelial wound settings. We will use infectious entry assays (detection of viral transcription or pseudo-genome expression) coupled with biochemical and genetic cell manipulations to define the mechanisms of HPV infection of normal host HKs. Quantitative multi-parameter confocal, super-resolution and video microscopy will permit us to visualize the fate of HPVs and localize the viruses with cell proteins under genetic and biochemical conditions that prevent infectious entry. We will combine the techniques described above with cell culture and mouse models of infection where epithelial wounding can be induced to examine how wounding contributes to HPV infections. Three inter-related SPECIFIC AIMS will address our central hypothesis. In Aim 1 we will determine function of EGFR in onco-HPV entry into HKs. In Aim 2 we will define how the interplay between EGFR and A2t promotes the uptake of onco-HPVs into HKs. In Aim 3 we will assess the roles of EGFR and A2t in HPV entry in keratinocytes using in vitro and in vivo wound models. Hypotheses regarding specific aspects of HPV-HK interactions, EGFR and AnxA2 activities and HPV entry are posed. Whether our theories are supported or refuted, we will increase our understanding of the molecular mechanisms of HPV-host cell interactions, the biology of HK uptake, and EGFR regulation in HKs, each of which are poorly understood. This fundamental science program may also inform strategies for preventing persistent onco-HPV infections, a major risk for morbidity and malignant progression. As EGFR and AnxA2 are important for other virus infections, our results may be applicable to these pathogens as well. Lastly, we will gain needed insight into the cooperative functions of EGFR and A2t, both of which are dysregulated in many human diseases, including squamous cell cancers. !

项目摘要/摘要表皮生长因子受体（EGFR）在上皮伤口愈合，细胞生长中具有关键的调节作用和许多哺乳动物细胞类型的细胞存活。 EGFR被许多人类病毒劫持，包括人类乳头瘤病毒（HPV），以促进其传染性进入宿主细胞。然而，特定机制 EGFR激活导致病毒体内化的理解很少。 HPV类型16和31与 EGFR和EGFR相互作用的伴侣，Annexin A2 Tetramer（A2T），在HK质膜上。我们的科学前提是基于我们实验室和其他群体的发现：EGFR或A2T的功能抑制蛋白质可显着降低HKS中的HPV进入和感染。我们的中心假设是EGFR 信号传导促进A2T向外部细胞膜的易位以启动HPV的传染性进入进入宿主细胞。我们将定义EGFR及其信号在促进HKS摄取HPV的作用，以及确定EGFR是否直接参与ONCO-HPV内在化。我们还将研究A2T 与EGFR信号合作，以促进Onco-HPV的传染性进入。上皮伤害重要但知之甚少，但知之甚少，在体内乳头瘤病毒感染中的作用。值得注意的是，EGFR和A2T是在上皮伤口设置中激活。我们将使用传染性入学分析（检测病毒转录或伪基因组表达）与生化和遗传细胞操作结合以定义正常宿主HKS的HPV感染机制。定量多参数共焦，超分辨率和视频显微镜将使我们能够可视化HPV的命运，并将病毒与细胞蛋白定位在下面防止传染性进入的遗传和生化条件。我们将结合描述的技术上面的细胞培养和小鼠感染模型，可以诱导上皮伤口检查以检查伤害如何导致HPV感染。三个相互关联的特定目标将解决我们的中心假设。在AIM 1中，我们将确定EGFR在ONCO-HPV进入HKS中的功能。在目标2中，我们将定义EGFR和A2T之间的相互作用是如何促进Onco-HPV对HKS的吸收。在目标3中，我们将使用体外和体内伤口模型评估EGFR和A2T在角质形成细胞中HPV进入中的作用。关于HPV-HK相互作用，EGFR和ANXA2活动以及HPV进入的特定方面的假设是摆姿势。无论我们的理论得到支持还是被驳斥，我们都将增加对分子的理解 HPV宿主相互作用的机制，HK摄取的生物学和HKS中的EGFR调节这是很熟悉的。该基本科学计划还可以为防止持续的Onco-HPV感染，发病率和恶性发展的主要风险。作为EGFR和ANXA2 对于其他病毒感染至关重要，我们的结果也可能适用于这些病原体。最后，我们将获得对EGFR和A2T合作功能的所需洞察力，这两者都失调许多人类疾病，包括鳞状细胞癌。呢

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Infectious titres of human papillomaviruses (HPVs) in patient lesions, methodological considerations in evaluating HPV infectivity and implications for the efficacy of high-level disinfectants.

DOI：
10.1016/j.ebiom.2020.103165
发表时间：
2021-01
期刊：
EBioMedicine
影响因子：
11.1
作者：
Ozbun MA;Bondu V;Patterson NA;Sterk RT;Waxman AG;Bennett EC;McKee R;Sharma A;Yarwood J;Rogers M;Eichenbaum G
通讯作者：
Eichenbaum G