Immunopathogenesis of Group A Streptococcal Infection

A 族链球菌感染的免疫发病机制

• 批准号: 7190459
• 负责人: rita kansal
• 金额: $ 40.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190459
• 关键词: Abbreviations; Address; Alleles; Antibodies; Antigen-Presenting Cells; Antigens; Attention; Bacteria; Bacterial Infections; Binding; Biochemical; Class; Clinical; Communicable Diseases; Complex; Disease; Disease Outcome; Funding; Future; Gene Deletion; Genes; Genetic; Goals; Haplotypes; Histocompatibility Antigens Class II; Human; Human Identifications; Hypotension; Immunogenetics; Immunologics; In Vitro; Individual; Infection; Inflammatory Response; Inflammatory Response Pathway; Integration Host Factors; Invasive; Knock-out; Lead; Link; MHC Class II Genes; Mammalian Genetics; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Nature; Necrotizing fasciitis; Organ failure; Organism; Outcome; Pathogenesis; Patients; Pattern; Period Analysis; Peripheral Blood Mononuclear Cell; Pharyngitis; Play; Predisposition; Principal Investigator; Process; Range; Recombinants; Recrudescences; Risk; Role; Serotyping; Severities; Shock; Signal Transduction; Streptococcal Infections; Streptococcus; Streptococcus pyogenes; Superantigens; Systemic disease; T-Lymphocyte; Testing; Toxic Shock Syndrome; Transgenic Mice; Transgenic Organisms; Variant; Virulence; Virulence Factors; Work; bacterial genetics; base; design; erythrogenic toxin; fluorouracil/semustine/vincristine protocol; genetic association; in vivo; insight; mortality; mutant; pathogen; programs; receptor; response; therapeutic vaccine; tool; vaccine development

DESCRIPTION (provided by applicant): The overall goal of the present application is to explore the way specific host genetic factors and specific bacterial virulence determinants interact together to influence the outcome of an important infectious disease. This paradigm is critical to explain the wide variety of potential outcomes that occur when a human host encounters a potentially pathogenic organism like Group A streptococcus (GAS), from asymptomatic colonization to mild infection to severe morbidity or mortality. The model we have developed studies GAS-induced severe systemic disease (SSD; the bacterial superantigens (SAgs) that are key players in eliciting SSD; and the host factors involved are the HLA class II molecules that present the SAgs to T cells. The pathogenic link of the host genetic and bacterial virulence factors is clear, since the HLA molecules are receptors for SAgs, presenting them to the TCR and transmitting biochemical signals into APCs. We found that the host immunogenetic makeup influences the clinical outcome of invasive GAS disease. Specific HLA class II haplotypes conferred strong protection from the severe forms of the invasive disease, while others increased the risk for SSD. We also determined the underlying mechanism for these genetic associations by demonstrating that the presentation of Strep SAgs by the class II DRB1( 1501/DQB1*0602 haplotype, which was strongly associated with protection from SSD (P=0.0007), elicited significantly lower inflammatory responses as compared to their presentation by either risk or neutral haplotypes (P<0.0001). Patients with this protective haplotype mounted significantly reduced responses to the Strep SAgs (low responders) and were less likely to develop SSD. By contrast patients who lacked this protective haplotypes or had the DRB1*14/DQB1*0503 high risk haplotype were high responders to the Strep SAgs and were more likely to develop SSD. Our working hypothesis is that HLA class II association with risk/protection from SSD is the same for patients with invasive infections caused by particular GAS serotypes that are commonly isolated from invasive GAS infections and that share a similar SAg repertoire. The robust nature of our model is manifested in our initial identification human HLA haplotypes associated with high-risk and protection against GAS associated SSD. In this application, our combined bacterial and mammalian genetic approach will allow identification of how specific GAS SAg/human HLA combinations determine risk for a particular disease outcome. It is our hope that these results will inform the future design and application of specific therapeutic and vaccine strategies against GAS infection, and serve as a model for investigating the complex pathogenesis of other human bacterial infections.

描述（由申请人提供）：本申请的总体目标是探索特定宿主遗传因素和特定细菌毒力决定因素相互作用以影响重要传染病的结果的方式。这种范式对于解释人类宿主遇到诸如A组链球菌（气体）（从无症状的定殖到轻度感染到严重的发病率或死亡率）等潜在的致病生物等潜在的致病生物（如AS链球菌（气体））的各种潜在结果至关重要。我们开发了研究气体引起的严重全身性疾病的研究模型（SSD；细菌超抗原（SAG），它们是引起SSD的主要参与者；涉及的宿主因素是HLA II级分子，它们呈现出T细胞的垂直分子。宿主遗传和细菌病毒因子的病原体与HLA MERECES呈现了Hla Moreculs，因为它是宿主遗传和细菌病毒因子的病原体联系。将生化信号传播到APC中。 1501/dqb1*0602单倍型与SSD的保护密切相关（P = 0.0007），与风险或中性单倍型相比，其炎症反应显着降低了炎症反应（P <0.0001）。具有这种保护性单倍型的患者可显着减少对链球菌下垂（低反应者）的反应，并且不太可能发展SSD。相比之下，缺乏这种保护性单倍型或具有DRB1*14/DQB1*0503高风险单倍型的患者是对链球菌下垂的高反应者，并且更有可能发展SSD。 我们的工作假设是，HLA II类与SSD风险/保护的II级关联对于由特定气体血清型引起的侵入性感染的患者相同，通常是从侵入性气体感染中分离出来的，并且具有类似的SAG曲目。 我们的模型的强大性质在我们的初始识别人类HLA单倍型与高风险和针对气体相关SSD的保护相关的人类HLA单倍型中表现出来。在此应用中，我们组合的细菌和哺乳动物遗传方法将允许识别特定的气体SAG/人HLA组合如何确定特定疾病结果的风险。我们希望这些结果将为针对天然气感染的特定治疗和疫苗策略的未来设计和应用提供信息，并作为研究其他人类细菌感染的复杂发病机理的模型。

项目成果

Unbiased forward genetics and systems biology approaches to understanding how gene-environment interactions work to predict susceptibility and outcomes of infections.

采用无偏见的正向遗传学和系统生物学方法来了解基因-环境相互作用如何预测感染的易感性和结果。

• DOI: 10.1002/9780470696781.ch12
• 发表时间: 2008
• 期刊: Novartis Foundation symposium
• 作者: Kotb,Malak;Fathey,Nourtan;Aziz,Ramy;Rowe,Sarah;Williams,RobertW;Lu,Lu
• 通讯作者: Lu,Lu

Failure of viridans group streptococci causing bacteremia in pediatric oncology patients to express superantigens.

草绿色群链球菌导致儿科肿瘤患者菌血症无法表达超抗原。

• DOI: 10.1097/01.mph.0000212986.41564.e9
• 发表时间: 2006
• 期刊: Journal of pediatric hematology/oncology
• 作者: Ohuoba,EsobeF;Kansal,RitaG;Hayden,RandallT;Kotb,Malak;Adderson,ElisabethE
• 通讯作者: Adderson,ElisabethE

Microevolution of group A streptococci in vivo: capturing regulatory networks engaged in sociomicrobiology, niche adaptation, and hypervirulence.

• DOI: 10.1371/journal.pone.0009798
• 发表时间: 2010-04-14
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Aziz RK;Kansal R;Aronow BJ;Taylor WL;Rowe SL;Kubal M;Chhatwal GS;Walker MJ;Kotb M
• 通讯作者: Kotb M

Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity.

侵袭性 A 族链球菌感染发病机制中的危险因素：保护性体液免疫的作用。

• DOI: 10.1128/iai.67.4.1871-1877.1999
• 发表时间: 1999
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Basma,H;Norrby-Teglund,A;Guedez,Y;McGeer,A;Low,DE;El-Ahmedy,O;Schwartz,B;Kotb,M
• 通讯作者: Kotb,M