Mechanisms Underlying Clearance of Persistent Infections and Tumors

清除持续感染和肿瘤的机制

• 批准号: 10265216
• 负责人: Dorian McGavern
• 金额: $ 242.7万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265216
• 关键词: Adaptive Immune System; Adoptive Immunotherapy; Adult; Affect; Anatomy; Antibodies; Antiviral Agents; Antiviral Response; Area; Birth; Blood; Brain; Brain Neoplasms; Cells; Cultured Cells; Data; Dendritic Cells; Disease; Engraftment; Equilibrium; Future; Glioblastoma; HIV; HIV-1; Health; Homeostasis; Host Defense; Human; Immune; Immune system; Immunity; Immunologic Factors; Immunologics; Impairment; In Situ; In Vitro; Infection; Infectious Diseases Research; Intention; Interferon Type I; Interferons; Intravenous; Laboratories; Lymphocytic choriomeningitis virus; Lytic; Meningeal; Meninges; Microbe; Modeling; Mus; Nervous System Physiology; Neuraxis; Peripheral; Play; Property; Proteins; Research; Resolution; Role; Serum; Shapes; System; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Tissues; Viral; Virion; Virus; Virus Diseases; adaptive immune response; antimicrobial; central tolerance; chronic infection; design; disorder control; exhaustion; human pathogen; immunopathology; immunoregulation; imprint; in utero; in vivo; infectious disease model; interest; macrophage; monocyte; neoplastic cell; pathogen; preservation; prevent; purge; response; sensor; tumor; tumor immunology; virus envelope

Persistent viruses, such as human immunodeficiency virus (HIV), cause major health problems worldwide and are extraordinarily difficult to clear following the establishment of persistence. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage to the host. We model states of persistent infection in our laboratory using lymphocytic choriomeningitis virus (LCMV), a mouse as well as human pathogen. Persistent LCMV infections can be established by infecting mice in utero or by infecting adult mice intravenously with specific strains of the virus. When mice are persistently infected at birth or in utero with LCMV, the virus establishes systemic persistence, infecting both peripheral tissues as well as the central nervous system (CNS). Adult LCMV carrier mice are centrally tolerant to the virus at the T cell level and thus unable to eradicate the pathogen. We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 infection in humans, including infection / impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. Both models LCMV persistence allow us to study how the immune system can be manipulated or supplemented to control a persistent viral infection in the periphery and CNS. One area of active research in the laboratory is the study of immune factors that control viral infections in the periphery and prevent their entry into the CNS. We recently studied a type I interferon (IFN-I)-inducible antiviral protein referred to as tetherin or BST-2. This host defense protein plays an important role in inhibiting the cellular release of many enveloped viruses, including HIV-1. To determine how this protein shapes the early antiviral defense to a persistent infection, we studied its role in the LCMV clone 13 model. Interestingly, we uncovered in vitro that BST-2 has only a modest affect on the release of LCMV virions from cultured cells. However, the antiviral effect of BST-2 is far more significant in vivo. In its absence, a persistence-prone strain of LCMV (clone 13) is no longer confined to the splenic marginal zone within the first few days of infection. Splenic marginal zone macrophages express BST-2 in response to IFN-I and likely use this protein to sequester viruses like LCMV that are captured from the blood. BST-2 deficiency allows LCMV clone 13 to quickly escape from the marginal zone, resulting in an altered distribution of LCMV-specific T cells and reduced T cell proliferation / function. This also delays viral control in the serum and promotes long-term viral persistence in the brain. These data demonstrate that BST-2 has an important role in shaping the anatomical distribution and adaptive immune response against a persistent viral infection in vivo. Another aspect of our infectious disease research is to understand how tissues like the CNS return to homeostasis after a pathogen is cleared. We discovered that resolution of viral infection in the meninges is associated with peripheral immune cell engraftment. Under steady state, the meninges are inhabited by long-lived tissue resident macrophages. Upon viral infection, we observed that the meninges become heavily infiltrated by peripheral monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. These cells possessed functional properties that were different than those of resident meningeal macrophages, including a loss of bacterial and immunoregulatory sensors. These data demonstrate that even clearance of an infection can imprint a tissue with new functional properties and alter its ability to respond to future challenges. Conceptually, this finding adds a new level of complexity to our understanding of how diseases could develop after a pathogen is cleared. More recently, we have entered the field of tumor immunology, attempting to understand how the innate and adaptive systems engage glioblastomas. These rapidly growing tumors are uniformly fatal and impose considerable challenges on the brain resident and peripheral immune systems. Our current understanding of anti-microbial immunity is that the CNS parenchyma prefers utilization of non-cytolytic effector mechanisms when attempting to control a pathogen. We have demonstrated in multiple models of infectious disease that control of CNS microbes, both by antibodies and T cells, can occur with minimal immunopathology. These mechanisms favor preservation of the infected CNS but give tumor cells an opportunity to grow unchecked in this compartment. In fact, we have observed that CNS imposed utilization of non-cytolytic immune effector mechanism is relatively ineffective against a glioblastoma. We are therefore seeking to leverage successful antiviral responses observed in less constrained peripheral tissues against brain tumors. We believe that this approach is required to overcome a rapidly growing tumor like a glioblastoma.

持续性病毒，例如人类免疫缺陷病毒（HIV），在全球范围内引起重大健康问题，并且在建立持久性后难以清除。鉴于与清除持续感染相关的挑战，重要的是要开发和机械理解的治疗策略，这些策略成功地消除了病毒性，而不会诱导宿主永久损害。 我们使用淋巴细胞脉络膜宿主性炎病毒（LCMV），小鼠和人类病原体对实验室中持续感染的状态进行建模。 持续的LCMV感染可以通过在子宫内感染小鼠或通过特异性病毒菌株静脉内感染成年小鼠来建立。 当小鼠在出生时或用LCMV的子宫内持续感染时，该病毒会建立全身性持久性，感染外围组织以及中枢神经系统（CNS）。成年LCMV载体小鼠在T细胞水平上对病毒的中心耐受性，因此无法消除病原体。 We model persistent infection in adult mice by infecting with more aggressive strains of LCMV such as clone 13. Infection with clone 13 initiates a state of persistence that shares some important features with HIV-1 infection in humans, including infection / impairment of dendritic cells, exhaustion / deletion of the virus-specific T cells, and rapid establishment of viral persistence in the CNS as well as peripheral tissues. 这两种模型LCMV持久性都使我们能够研究如何操纵或补充免疫系统，以控制周围和中枢神经系统中持续的病毒感染。 实验室积极研究的一个领域是对控制周围病毒感染并防止其进入中枢神经系统的免疫因子的研究。 我们最近研究了一种I型干扰素（IFN-I）诱导的抗病毒蛋白，称为Tetherin或BST-2。 该宿主防御蛋白在抑制包括HIV-1在内的许多包膜病毒的细胞释放中起着重要作用。为了确定这种蛋白质如何塑造早期抗病毒防御持续感染，我们研究了其在LCMV克隆13模型中的作用。有趣的是，我们在体外发现了BST-2对培养细胞中LCMV病毒体释放的影响只有适中的影响。但是，BST-2的抗病毒作用在体内更为重要。在缺席的情况下，在感染后的头几天内，LCMV的持续性持续应力（克隆13）不再局限于脾脏边缘区。 脾脏边缘区巨噬细胞响应IFN-I响应BST-2，并可能使用该蛋白质来隔离从血液中捕获的LCMV等病毒。 BST-2缺乏使LCMV克隆13迅速从边际区域逃脱，从而导致LCMV特异性T细胞的分布改变，并减少T细胞增殖 /功能。 这也延迟了血清中的病毒控制，并促进了大脑中的长期病毒持久性。 这些数据表明，BST-2在塑造对体内持续病毒感染的解剖分布和适应性免疫反应中具有重要作用。 我们传染病研究的另一个方面是了解在病原体清除病原体后，诸如中枢神经系统之类的组织如何恢复体内平衡。我们发现脑膜中病毒感染的分辨率与外周免疫细胞植入有关。 在稳定状态下，这些脑膜被长寿命的驻留巨噬细胞居住。病毒感染后，我们观察到脑膜被周围单核细胞大量渗透，这些单核细胞植入了脑膜细胞，并在病毒清除后保持了几个月的位置。 这些细胞具有与常驻脑膜巨噬细胞不同的功能特性，包括细菌和免疫调节传感器的丧失。 这些数据表明，即使是感染的清除也可以使组织具有新的功能特性，并改变其应对未来挑战的能力。从概念上讲，这一发现为我们对病原体清除后如何发展的理解增加了新的复杂程度。 最近，我们进入了肿瘤免疫学领域，试图了解先天和适应性系统如何与胶质母细胞瘤互动。 这些快速生长的肿瘤是致命的，并在大脑常驻和周围免疫系统上构成了巨大的挑战。 我们目前对抗微生物免疫力的理解是，CNS实质更喜欢在尝试控制病原体时使用非溶解效应器机制。 我们已经在多种传染病模型中证明了通过抗体和T细胞控制中枢神经系统微生物的控制，可能会以最小的免疫病理学发生。 这些机制有利于保存感染的中枢神经系统，但为肿瘤细胞提供了在此隔室中不受限制地成长的机会。实际上，我们已经观察到，中枢神经系统对非溶质免疫效应子机制的利用相对无效，针对胶质母细胞瘤。 因此，我们正在寻求利用在脑肿瘤对周围组织较少的较少受限的周围组织中观察到的成功的抗病毒反应。 我们认为，需要这种方法来克服像胶质母细胞瘤这样的快速生长的肿瘤。