Structure and Function of Natural Killer Cell Receptors

自然杀伤细胞受体的结构和功能

• 批准号: 7459922
• 负责人: Roy A Mariuzza
• 金额: $ 4.74万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459922
• 关键词: Activated Natural Killer Cell; Adult; Affinity; Argentina; Binding; Binding Sites; CD8B1 gene; Cadherins; Cell Adhesion Molecules; Cell Wall; Cell physiology; Cells; Code; Collaborations; Complex; Cytomegalovirus; Development; Discrimination; Disseminated Malignant Neoplasm; E-Cadherin; Equilibrium; Evolution; Genome; Goals; Grant; Herpesviridae Infections; Histocompatibility Antigens Class I; Human; Immune response; Immune system; Immunocompromised Host; Individual; Infection; KLRA1 gene; Knowledge; Lectin; Libraries; Life; Ligands; Ly49P receptor; MHC Class I Genes; MHC Class II Genes; Mediating; Medical Surveillance; Molecular; Murid herpesvirus 1; Mus; Natural Killer Cells; Natural killer triggering receptor; Nature; Neonatal; Pathway interactions; Pattern recognition receptor; Peptides; Peptidoglycan; Play; Production; Property; Proteins; Purpose; Research; Role; Signal Transduction; Solutions; Structure; Surface; System; T-Cell Receptor; T-Lymphocyte; Today; Transfection; United States National Institutes of Health; Universities; Variant; Viral; Viral Proteins; Virus; Virus Diseases; Yeasts; analog; base; cancer cell; cytotoxicity; dimer; insight; killings; microbial; parent grant; pathogen; peptidoglycan recognition protein; prevent; receptor; receptor binding; stoichiometry

DESCRIPTION (provided by applicant): During evolution viruses have developed an array of mechanisms to escape surveillance by the immune system, including production of decoy proteins that mimic the host's molecules for the purpose of avoiding nonself recognition. The murine cytomegalovirus (MCMV) genome codes for an MHC class I-like molecule, m157, which binds the inhibitory NK cell receptor Ly49I. The m157 protein is displayed on the surface of MCMV-infected cells to prevent NK cell attack. We will carry out biophysical and structural studies of the interaction of the inhibitory receptor Ly49I with the viral protein m157. The immune system counterattacks with activating NK receptors, such as Ly49H, that activate NK cells once they encounter m157 decoy molecules on the surface of target cells. This interaction protects the host against viral infection by killing the infected cell. We will conduct research to understand the biophysical and structural basis for the interaction of the activating receptor Ly49H with the MCMV protein m157. In addition, MCMV somehow modifies the MHC class I molecule H-2Dk expressed on an infected cell in a manner that induces NK cells carrying the activating Ly49P receptor to kill the target cell. To understand the nature of this mechanism, whereby "modified self" resists a pathogen infection, we will determine the crystal structures of the activating receptor Ly49P in complex with H-2Dk loaded with viral or self peptides. KLRG1, a lectin-like receptor found in both human and mouse, is an inhibitory NK cell and CD8+ T cell receptor over-expressed during viral infection. We will analyze the binding properties and determine the crystal structure of KLRG1 in complex with its cognate ligands, the adhesion molecules N-, R- and E-cadherin. The KLRG1-cadherin interaction is believed to play a role in the killing of virally infected and metastatic cancer cells. We expect that the proposed studies will define the molecular basis for the interaction of NK cell receptors with both viral (m157) and host (MHC class I, cadherins) ligands that regulate NK cell activity during the course of viral infections. This research will be done primarily in Argentina at the University of Buenos Aires in collaboration with Dr. Emilio Malchiodi, as an extension of NIH Grant R01 AI047990-07 (Mariuzza; 7/1/2004-6/30/2009). More than 3 billion people today live with cytomegalovirus (CMV, Herpesviridae) infection. Viral and host mechanisms have coevolved to enable the pair to live in a mutually tolerant relationship in most infected individuals, but the virus is pathogenic in neonatal life and in adults who are immunocompromised. Natural killer (NK) cells play a central role in innate immune responses to a variety of virally infected or malignant cells. NK cell function is regulated by a dynamic balance between activating and inhibitory receptors that interact with specific ligands. The goal of this proposal is to obtain structural insights into the interaction of murine NK cell receptors with viral or host ligands that regulate NK cell function during the course of viral infections. Such knowledge may contribute to the development of new strategies for the treatment of viral infections based on modulation of NK cell cytolytic activity.

描述（由申请方提供）：在进化过程中，病毒已经开发出一系列机制来逃避免疫系统的监视，包括产生诱饵蛋白，其模仿宿主的分子以避免非自我识别。鼠巨细胞病毒（MCMV）基因组编码MHC I类分子m157，其结合抑制性NK细胞受体Ly 49 I。m157蛋白展示在MCMV感染细胞的表面上，以防止NK细胞攻击。我们将进行抑制性受体Ly 49 I与病毒蛋白m157相互作用的生物物理和结构研究。免疫系统通过激活NK受体（如Ly 49 H）进行反击，一旦NK细胞遇到靶细胞表面上的m157诱饵分子，就会激活NK细胞。这种相互作用通过杀死受感染的细胞来保护宿主免受病毒感染。我们将进行研究，以了解激活受体Ly 49 H与MCMV蛋白m157相互作用的生物物理和结构基础。此外，MCMV以某种方式修饰在感染细胞上表达的MHC I类分子H-2Dk，其方式诱导携带活化Ly 49 P受体的NK细胞杀死靶细胞。为了理解这种机制的本质，即“修饰的自我”抵抗病原体感染，我们将确定活化受体Ly 49 P与H-2Dk复合的晶体结构，H-2Dk装载有病毒或自我肽。KLRG 1是一种在人类和小鼠中发现的凝集素样受体，是一种在病毒感染期间过表达的抑制性NK细胞和CD 8 + T细胞受体。我们将分析结合特性，并确定KLRG 1与其同源配体，粘附分子N-，R-和E-钙粘蛋白复合物的晶体结构。KLRG 1-钙粘蛋白相互作用被认为在杀死病毒感染和转移性癌细胞中起作用。我们预计，拟议的研究将确定NK细胞受体与病毒（m157）和宿主（MHC I类，钙粘蛋白）配体相互作用的分子基础，这些配体在病毒感染过程中调节NK细胞活性。这项研究将主要在阿根廷布宜诺斯艾利斯大学与Emilio Malchiodi博士合作完成，作为NIH Grant R 01 AI 047990 -07的扩展（Mariuzza; 2004年7月1日至2009年6月30日）。今天，超过30亿人患有巨细胞病毒（CMV，疱疹病毒科）感染。病毒和宿主机制共同进化，使这对病毒在大多数感染个体中生活在相互容忍的关系中，但病毒在新生儿和免疫功能低下的成年人中具有致病性。自然杀伤（NK）细胞在对各种病毒感染或恶性细胞的先天免疫应答中发挥核心作用。NK细胞功能受与特异性配体相互作用的激活性和抑制性受体之间的动态平衡调节。该提案的目标是获得结构的见解，在病毒感染过程中调节NK细胞功能的病毒或宿主配体的小鼠NK细胞受体的相互作用。这些知识可能有助于开发基于NK细胞溶细胞活性调节的病毒感染治疗新策略。

项目成果

Engineered trivalent immunogen adjuvanted with a STING agonist confers protection against Trypanosoma cruzi infection.

• DOI: 10.1038/s41541-017-0010-z
• 发表时间: 2017
• 期刊: NPJ vaccines
• 影响因子: 9.2
• 作者: Sanchez Alberti A;Bivona AE;Cerny N;Schulze K;Weißmann S;Ebensen T;Morales C;Padilla AM;Cazorla SI;Tarleton RL;Guzmán CA;Malchiodi EL
• 通讯作者: Malchiodi EL

Tc52 amino-terminal-domain DNA carried by attenuated Salmonella enterica serovar Typhimurium induces protection against a Trypanosoma cruzi lethal challenge.

减毒肠沙门氏菌鼠伤寒血清型携带的 Tc52 氨基末端结构域 DNA 可诱导针对克氏锥虫致命攻击的保护。

• DOI: 10.1128/iai.02190-14
• 发表时间: 2014
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Matos,MarinaN;Cazorla,SilviaI;Bivona,AugustoE;Morales,Celina;Guzmán,CarlosA;Malchiodi,EmilioL
• 通讯作者: Malchiodi,EmilioL

Uptake and intracellular trafficking of superantigens in dendritic cells.

• DOI: 10.1371/journal.pone.0066244
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ganem MB;De Marzi MC;Fernández-Lynch MJ;Jancic C;Vermeulen M;Geffner J;Mariuzza RA;Fernández MM;Malchiodi EL
• 通讯作者: Malchiodi EL