Understanding oncogenic human papillomavirus persistence and immune modulation in tonsil epithelia

了解致癌人乳头瘤病毒在扁桃体上皮中的持久性和免疫调节

• 批准号: MR/Y001753/1
• 负责人: Joanna Parish
• 金额: $ 71.02万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001753%2F1
• 关键词: Understanding; oncogenic; human; papillomavirus; persistence

Viruses are obligate intracellular parasites that have evolved to manipulate the target cell and local tissue environment to facilitate replication. Some viruses can establish persistent, sub-clinical infection of target cells and these infections can evade host immune detection and exist for decades. Human papillomaviruses (HPV) are a family of viruses that infect the moist and dry surfaces of human skin. The target cell of infection is a specific type of skin cell called a keratinocyte. Infection with many different types of HPV results in the formation of warts but persistent infection with a subset of HPV types, so called high-risk HPV, is the cause of cancers of anal and genital regions of the body (including the uterine cervix), and cancers of the head and neck, specifically in the tonsils and base of tongue, collectively known as the oropharynx. Although robust strategies exist to prevent high-risk HPV infection and to detect pre-cancerous lesions through vaccination and national cervical screening programmes, these measures are not available in all countries. Indeed, the number of HPV-associated cancers has remained at around 600,000 cases per year worldwide despite screening and vaccination. Furthermore, the incidence of HPV-driven oropharyngeal cancer is increasing in patients that are younger, predominantly male and non-smokers. The primary site of oropharyngeal HPV infection is the tonsil, a organ rich in immune cells that serve to detect invading pathogens and prevent respiratory and gastrointestinal infection. Establishment of persistent high-risk HPV infection in the tonsil must therefore require strong suppression of local immune cell activation. The majority (greater than 90%) of HPV-positive oropharyngeal cancers are caused by HPV type 16 (HPV16). While HPV16 is also the most common HPV found in cervical cancers (~60%) the burden is much less than for oropharyngeal cancers. Another high-risk type, HPV18 accounts for ~15% of cervical cancers but is rarely found in oropharyngeal cancers. The reasons for this disparity in disease association at different body sites are not known. Our preliminary data suggest that HPV16, but not HPV18, is able to suppress the production of immune activating molecules by reprogramming gene expression of the host tonsil keratinocyte. Using state-of-the-art primary cell-based models of HPV infection and cutting-edge DNA and gene sequencing methods, we will investigate the similarities and differences in HPV16 and HPV18 life cycles in tonsil keratinocytes. We will determine how HPV16 suppresses host immune detection through repression of key pathways that activate and attract local immune cells to the site of infection. We will then use our expertise in primary cell culture to combine primary keratinocytes with donor-matched lymphoidal tissue, which contains to tonsillar immune cells, to establish in vitro tonsil organ-like cultures that will be used to study immune cell activation and migration in response to HPV infection. The results of this project will uncover novel mechanisms of HPV persistence in the tonsil. We will also determine the key differences in immune suppression by cancer-causing HPV16 and HPV18 and how these differences contribute to local immune cell activation and viral clearance. This is important as there is a critical need to understand how HPV16 can persist and induce cancer within the immune-rich oropharynx to enable the development of novel (immuno-) therapies to combat HPV-driven cancers.

病毒是专性细胞内寄生虫，已进化为操纵靶细胞和局部组织环境以促进复制。一些病毒可以对靶细胞建立持久的亚临床感染，这些感染可以逃避宿主免疫检测并存在数十年。人乳头瘤病毒 (HPV) 是感染人类皮肤潮湿和干燥表面的病毒家族。感染的靶细胞是一种特殊类型的皮肤细胞，称为角质形成细胞。感染许多不同类型的 HPV 会导致疣的形成，但持续感染 HPV 类型的子集（即所谓的高危 HPV）是导致肛门和生殖器区域（包括子宫颈）癌症的原因。头颈癌，特别是扁桃体和舌根癌，统称为口咽癌。尽管存在强有力的策略来预防高危 HPV 感染并通过疫苗接种和国家宫颈筛查计划来检测癌前病变，但并非所有国家都提供这些措施。事实上，尽管进行了筛查和疫苗接种，全球每年 HPV 相关癌症的数量仍保持在 60 万例左右。此外，在年轻患者（主要是男性和非吸烟者）中，HPV 驱动的口咽癌的发病率正在增加。口咽部 HPV 感染的主要部位是扁桃体，这是一种富含免疫细胞的器官，可以检测入侵的病原体并预防呼吸道和胃肠道感染。因此，扁桃体中持续高危 HPV 感染的建立必须需要强力抑制局部免疫细胞的激活。大多数（超过 90%）HPV 阳性口咽癌是由 HPV 16 型 (HPV16) 引起的。虽然 HPV16 也是宫颈癌中最常见的 HPV（约 60%），但其负担远低于口咽癌。另一种高危类型 HPV18 约占宫颈癌的 15%，但在口咽癌中很少发现。不同身体部位的疾病关联存在这种差异的原因尚不清楚。我们的初步数据表明，HPV16（而非 HPV18）能够通过重新编程宿主扁桃体角质形成细胞的基因表达来抑制免疫激活分子的产生。使用最先进的基于原代细胞的 HPV 感染模型以及尖端的 DNA 和基因测序方法，我们将研究扁桃体角质形成细胞中 HPV16 和 HPV18 生命周期的异同。我们将确定 HPV16 如何通过抑制激活局部免疫细胞并将其吸引到感染部位的关键途径来抑制宿主免疫检测。然后，我们将利用我们在原代细胞培养方面的专业知识，将原代角质形成细胞与供体匹配的淋巴组织（其中含有扁桃体免疫细胞）结合起来，建立体外扁桃体器官样培养物，用于研究免疫细胞的激活和迁移反应HPV 感染。该项目的结果将揭示 HPV 在扁桃体中持续存在的新机制。我们还将确定致癌 HPV16 和 HPV18 在免疫抑制方面的关键差异，以及这些差异如何促进局部免疫细胞激活和病毒清除。这一点很重要，因为迫切需要了解 HPV16 如何在免疫丰富的口咽部内持续存在并诱发癌症，以便开发新的（免疫）疗法来对抗 HPV 驱动的癌症。