Immune response to MCMV infection in the salivary glands

唾液腺对 MCMV 感染的免疫反应

• 批准号: 10735748
• 负责人: Laurent Brossay
• 金额: $ 80.17万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-12 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735748
• 关键词: Acute; Affect; Animal Model; Animals; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Calibration; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chronic; Coenzyme A; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease Progression; Dose; Effector Cell; Environment; Equilibrium; Evolution; Exhibits; Family member; Goals; Herpesviridae; Homologous Gene; Human; Human Herpesvirus 2; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunocompromised Host; Immunosuppression; Impairment; Individual; Infection; Inflammation; Interferons; Lymphocyte; Malignant Neoplasms; Modeling; Murid herpesvirus 1; Mus; Natural Killer Cells; Organ; PD-1 pathway; Phase; Population; Positioning Attribute; Pregnant Women; Primary Infection; Proliferating; Regulation; Reporting; Research; Salivary Glands; Site; Skin; Sorting; Species Specificity; Spleen; Symptoms; T-Lymphocyte; Therapeutic; Tissues; Tropism; Viral; Virus; Virus Diseases; cytotoxicity; design; experimental study; immunopathology; immunoregulation; improved; insight; interest; migration; neonate; pathogen; prevent; programmed cell death protein 1; receptor; recruit; recurrent infection; tool; tumor

The β-herpesvirus human cytomegalovirus (HCMV) infects around 50% of the world population. Although it remains asymptomatic in healthy individuals, it is never completely cleared from the host and can cause recurrent infections, especially at times of immunosuppression. HCMV poses the biggest threat to pregnant women, neonates, and immunocompromised individuals, whose symptoms tend to be more severe. The mouse homolog of HCMV, murine cytomegalovirus (MCMV), is a well-characterized animal model of viral infection. Like HCMV, MCMV has a tropism for the salivary glands (SMG) and persists in this organ for several months after primary infection. We have demonstrated that NK cells, which are critical in the spleen and blood, are hyporesponsive in the SMG, conceivably explaining the MCMV persistence in this organ. Interestingly, our preliminary data show that salivary gland NK cells regain normal effector functions against MCMV when relocated to different tissues, indicating that the salivary gland environment regulates NK cell function. MCMV exploits the SMG as the key site of viral persistence, which, similar to tumors, creates an immune environment with mechanisms to preclude excessive inflammation and/or tissue damage. Because the immune response to cancer and infection exhibit commonalities, we reasoned that the balance between pathogen clearance and immunopathology is likely to be regulated in part by checkpoint inhibitors within the salivary glands, especially during the persistence phase. Our data demonstrate that targeting KLRG1 improves the effector immune response to MCMV and survival at certain doses, but can lead to immunopathology depending on the dose. Our data also suggest that NK cells may inhibit CD8+ T cell recruitment, proliferation and effector functions in the salivary glands via the PD-1 pathway. This is supported by CITE-seq/TotalSeq on sorted T cells, showing expansion of unique CD8+ T cell clusters. Based on this preliminary data, we hypothesize that NK cells contribute to CMV control while preventing immunopathology by limiting the expansion of CD8+ T cells in the salivary glands. The overall goal of this proposal is to reveal the underlying mechanisms leading to MCMV persistence. In Specific Aim 1, we will investigate how the equilibrium between pathogen clearance and immunopathology is regulated. In Specific Aim 2, we will investigate how MCMV persistence is regulated in the salivary glands. In Specific Aim 3, we will investigate how NK cells inhibit T cell accumulation possibly limiting immunopathology in the salivary glands. We have generated a large number of tools to investigate the questions asked in this proposal. We are now in an excellent position to conduct the proposed studies. The results from these studies are likely to have relevance to infections caused by other viruses and aid in the design of strategies and therapeutics directed at manipulating effector cells during viral infection.

人类巨细胞病毒（HCMV）感染了世界上约50%的人口。虽然它在健康个体中保持无症状，但它从未从宿主中完全清除，并可引起复发性感染，特别是在免疫抑制时。HCMV对孕妇、新生儿和免疫功能低下者构成最大的威胁，他们的症状往往更严重。HCMV的小鼠同源物，鼠巨细胞病毒（MCMV），是一种良好表征的病毒感染动物模型。与HCMV一样，MCMV对唾液腺（SMG）具有嗜性，并在初次感染后持续数月。我们已经证明，NK细胞，这是关键的脾脏和血液中，是低反应的SMG，可以想象的解释MCMV的持久性在这个器官。有趣的是，我们的初步数据显示，唾液腺NK细胞重新定位到不同的组织时，对MCMV恢复正常的效应功能，表明唾液腺环境调节NK细胞的功能。MCMV利用SMG作为病毒持续存在的关键部位，其与肿瘤类似，产生具有防止过度炎症和/或组织损伤的机制的免疫环境。由于对癌症和感染的免疫反应具有共性，我们推断病原体清除和免疫病理学之间的平衡可能部分受到唾液腺内检查点抑制剂的调节，特别是在持续阶段。我们的数据表明，靶向KLRG 1在一定剂量下改善了对MCMV的效应免疫应答和存活率，但可能导致免疫病理学，这取决于剂量。我们的数据还表明，NK细胞可以通过PD-1途径抑制唾液腺中的CD 8 + T细胞募集、增殖和效应子功能。这在分选的T细胞上得到了CITE-seq/TotalSeq的支持，显示了独特的CD 8 + T细胞簇的扩增。基于这些初步数据，我们假设NK细胞有助于CMV控制，同时通过限制唾液腺中CD 8 + T细胞的扩增来预防免疫病理学。该提案的总体目标是揭示导致MCMV持续存在的潜在机制。在具体目标1中，我们将研究病原体清除和免疫病理学之间的平衡是如何调节的。在特定目标2中，我们将研究MCMV持续性在唾液腺中的调节方式。在具体目标3中，我们将研究NK细胞如何抑制T细胞积聚，可能限制唾液腺中的免疫病理学。我们已经开发了大量工具来调查本提案中提出的问题。我们现在处于进行拟议研究的最佳位置。这些研究的结果可能与其他病毒引起的感染有关，并有助于设计在病毒感染期间操纵效应细胞的策略和治疗方法。