HLA class II transgenic mouse models for S. aureus infections and superantigens

用于金黄色葡萄球菌感染和超抗原的 HLA II 类转基因小鼠模型

• 批准号: 8646845
• 负责人: CHELLA S DAVID
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646845
• 关键词: Address; Alleles; Animal Model; Antibiotic Resistance; Antibodies; Bacteria; Benign; Binding; Biochemical; Biological; Bone Marrow; Cells; Chimera organism; Clinical; Disease; Disease Outcome; Enterocytes; Exotoxins; Exposure to; Family; Functional disorder; Genetic Polymorphism; Goals; HLA-DQ Antigens; HLA-DQ6; HLA-DQ8 antigen; HLA-DR Antigens; HLA-DR2 Antigen; HLA-DR3 Antigen; HLA-DR4 Antigen; Health; Human; Immune response; Immunity; Immunologic Markers; Incidence; Individual; Infection; Infectious Skin Diseases; Inflammation; Institutes; Interferon Type II; Interferons; Intestines; Investigation; Kidney; Life; Liver; Lung; MHC Class II Genes; Mediating; Mediator of activation protein; Mind; Modeling; Molecular; Mouse Strains; Mus; Organ; Organism; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Play; Pneumonia; Prevention strategy; Production; Resistance; Role; Route; Sepsis; Series; Staphylococcal Enterotoxin B; Staphylococcus aureus; Streptococcus pyogenes; Superantigens; Syndrome; T-Cell Activation; T-Lymphocyte; TNFRSF10A gene; Therapeutic; Therapeutic Uses; Time; Toxic Shock Syndrome; Toxin; Transgenic Mice; Virulence; chemokine; cohort; cytokine; immunopathology; in vivo; insight; interest; methicillin resistant Staphylococcus aureus; mortality; mouse model; novel; receptor; resistant strain; response; weapons

DESCRIPTION (provided by applicant): Staphylococcus aureus is a ubiquitous Gram-positive organism implicated in a spectrum of diseases; from benign, localized skin infections to life-threatening, systemic illnesses including pneumonia, sepsis and menstrual or non-menstrual toxic shock syndromes (TSS). The virulence and pathogenicity of S. aureus is attributed to its several exotoxins. The superantigen exotoxins (SAg) are important amongst them because SAg are the most potent activators of T lymphocytes known. Certain SAg could also be used as biological weapons. Thus, SAg are important from many perspectives. Nonetheless, the molecular pathways by which SAg participate in the disease pathogenesis have not been completely understood due to lack of good animal models. The conventional mouse strains are resistant to TSS due to poor binding of SAg to mouse MHC class II. However, SAg binds more efficiently to human MHC (called HLA) class I molecules. Therefore, mice transgenically expressing HLA class II molecules readily succumb to the pathogenic effects of SAg delivered through different routes and to S. aureus infection. As the disease caused by SAg in HLA class II (HLA-DR3) transgenic mice also closely mimics the syndrome in humans, they are ideal models. Using this mouse model we have demonstrated that interferon-gamma (IFN-?) dependent small intestinal pathology plays a critical role in lethality associated with TSS. However, the molecular pathways by which INF-¿ contributes to lethality in TSS, either directly or indirectly through other mediators, are not clear. Therefore, it is proposed to (1) Delineate th mechanisms by which IFN-¿ plays a lethal role in staphylococcal SAg-induced TSS. This will be achieved by generating bone marrow chimeras between HLA-DR3.IFN-?R+/+ and HLA-DR3.IFN-?R-/- mice. Bone marrow chimeras will be challenged with SEB and several molecular pathways will be compared. However, IFN-? is also important for immunity S. aureus infections. Therefore, it is proposed to (2) Determine the role of IFN-? in the pathogenesis and immunity to MRSA-induced pneumonia and sepsis. This wil be accomplished by inducing pneumonia and sepsis in HLA-DR3.IFN-?+/+ and HLA-DR3.IFN-?R-/- mice with the MRSA isolate, USA300. Several bacteriological, immunological, biochemical and pathological parameters including mortality will be compared between these two lines of mice. It is known that HLA class II polymorphisms could strongly influence the magnitude of T cell activation and IFN-? production in response to streptococcal SAg. However, the impact of HLA-DR and HLA-DQ polymorphisms on staphylococcal SAg-driven immuneresponses has not been investigated. Therefore, it is proposed to (3) Determine the extent to which staphylococcal superantigen-induced IFN-? production is modulated by HLA class II polymorphisms thereby influencing the outcome of MRSA-induced pneumonia and sepsis. This will be investigated by a series of in vivo studies using transgenic mice expressing HLA-DR2, HLA-DR3, HLA-DR4, HLA-DQ2, HLA-DQ6 or HLA-DQ8 molecules.

描述（由申请人提供）：金黄色葡萄球菌是一种普遍存在的革兰氏阳性菌，与一系列疾病有关；从良性局部皮肤感染到危及生命的全身性疾病，包括肺炎、败血症和经期或非经期中毒性休克综合征。金黄色葡萄球菌的毒力和致病性归因于其几种外毒素（SAg）。其中，SAg 是已知的最有效的 T 淋巴细胞激活剂，因此，从许多角度来看，SAg 都很重要，但 SAg 参与疾病发病机制的分子途径尚不清楚。由于缺乏良好的动物模型，传统小鼠品系对 TSS 具有抵抗力，因为 SAg 与小鼠 MHC II 类分子的结合较差，但 SAg 与人类 MHC（称为 HLA）I 类分子的结合更有效。老鼠转基因表达 HLA II 类分子很容易受到通过不同途径传递的 SAg 和金黄色葡萄球菌感染的致病作用，因为 HLA II 类 (HLA-DR3) 转基因小鼠中由 SAg 引起的疾病也与人类的综合征非常相似，使用该小鼠模型，我们证明了干扰素-γ (IFN-?) 依赖性小肠病理学在 TSS 相关的致死性中发挥着关键作用。 INF-¿直接或通过其他介质间接导致 TSS 致死的机制尚不清楚，因此，建议 (1) 描述 IFN-¿ 的机制。在葡萄球菌 SAg 诱导的 TSS 中发挥致命作用，这将通过在 HLA-DR3.IFN-γR+/+ 和 HLA-DR3.IFN-γR-/- 小鼠之间产生骨髓嵌合体来实现。然而，IFN-α对于金黄色葡萄球菌感染的免疫作用也很重要。 IFN-α在MRSA诱导的肺炎和脓毒症的发病机制和免疫中的作用这将通过在HLA-DR3.IFN-α+/+和HLA-DR3.IFN-αR-/-小鼠中诱导肺炎和脓毒症来实现。 MRSA 分离株，USA300 将在这两个品系的小鼠之间比较一些细菌学、免疫学、生化和病理学参数，包括强烈的死亡率。众所周知，HLA II 类多态性可能影响感染的程度。对链球菌 SAg 的 T 细胞激活和 IFN-α 产生 然而，尚未研究 HLA-DR 和 HLA-DQ 多态性对葡萄球菌 SAg 驱动的免疫反应的影响。 HLA II 类多态性在多大程度上调节葡萄球菌超抗原诱导的 IFN-α 产生，从而影响 MRSA 诱导的肺炎的结果这将通过一系列体内研究来研究，使用表达 HLA-DR2、HLA-DR3、HLA-DR4、HLA-DQ2、HLA-DQ6 或 HLA-DQ8 分子的转基因小鼠。