Regulation of host inflammatory responses and outcome in melioidosis by TLR5

TLR5 对类鼻疽中宿主炎症反应和结果的调节

• 批准号: 9057608
• 负责人: Timothy Eoin West
• 金额: $ 32.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057608
• 关键词: Agonist; Alleles; Alveolar Macrophages; Animals; Biological; Blood; Breathing; Burkholderia pseudomallei; Candidate Disease Gene; Case Fatality Rates; Cell surface; Cells; Cessation of life; Clinical; Collaborations; Cutaneous; Data; Disease; Emerging Communicable Diseases; Employee Strikes; Epithelial Cells; Etiology; Flagellin; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genotype; Homozygote; Human; Human Genetics; Immune response; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; International; Ligands; Lipopolysaccharides; Lung; Mastigophora; Mediating; Melioidosis; Microarray Analysis; Mus; Organ; Organ failure; Organism; Other Genetics; Outcome; Pathway interactions; Patients; Phenotype; Plasma; Pneumonia; Primary Infection; Prospective Studies; Public Health; Regulation; Research; Research Personnel; Resources; Respiratory Tract Infections; Role; Rural; Sepsis; Signal Transduction; Soil; TLR4 gene; TLR5 gene; Testing; Thailand; Therapeutic Intervention; Time; Transgenic Mice; Translational Research; Variant; Work; burden of illness; cohort; cytokine; genetic variant; immune activation; improved; monocyte; mortality; neutrophil; novel; novel therapeutics; programs; receptor; response; sensor; therapy development; whole genome

DESCRIPTION (provided by applicant): Melioidosis is an often lethal emerging infectious disease caused by the Gram-negative soil saprophyte and putative bioweapon, Burkholderia pseudomallei. Endemic in northeast Thailand, mortality exceeds 40%. The disease results from inhalation or cutaneous inoculation with B. pseudomallei and most frequently presents with pneumonia and sepsis. Pneumonia confers over a two-fold increase in the odds of death. Melioidosis is representative of the huge global burden of pneumonia and sepsis in low resource settings, for which new therapies are urgently needed. We have identified a key role for Toll-like receptor 5 (TLR5), a cell surface flagellin sensor, in melioidosis. TLR5-deficiency accelerates death from respiratory infection in mice but a common human genetic variant in TLR5 that encodes a non-functional receptor is associated with dramatically improved survival in hospitalized patients with melioidosis. The variant is also associated with lower pro- inflammatory cytokine responses to B. pseudomallei upon stimulation of blood ex vivo. Although the only known ligand of TLR5 is flagellin, the reduced cytokine responses in carriers of the genetic variant are independent of B. pseudomallei flagellin and are also observed in response to B. pseudomallei lipopolysaccharide, a TLR4 agonist. These intriguing preliminary genetic data necessitate additional study of the mechanisms underlying the effect of the TLR5 genetic variant and the flagellin-TLR5 axis in melioidosis. The contrasting murine and human phenotypes emphasize the importance of performing translational science in humans. We hypothesize that an excessive host inflammatory response to this lung-tropic organism, regulated by TLR5 but independent of flagellin sensing, contributes to organ dysfunction and death in melioidosis patients. We will leverage the PI's translational melioidosis research program and robust collaboration with Thai investigators to test this hypothesis in three inter-related ways: 1) Determine whether the TLR5 genetic variant is associated with blunted innate immune activation, reduced inflammatory responses, and improved clinical outcome in melioidosis patients, 2) determine how TLR5 regulates inflammatory responses to B. pseudomallei in the lung, and 3) determine whether differential signaling mediated by the TLR5 genetic variant in B. pseudomallei infection is independent of flagellin sensing. A better understanding of TLR5 in melioidosis will increase the potential for therapeutic interventions and have ramifications for other etiologies of pneumonia and sepsis worldwide.

描述（由申请人提供）：Melioidosis是一种经常是由革兰氏阴性土壤腐生剂和假定的生物武器，Burkholderia pseudomallei引起的致命的新兴传染病。泰国东北部的地方病，死亡率超过40％。该疾病是由假芽孢杆菌吸入或皮肤接种引起的，最常出现肺炎和败血症。肺炎的死亡几率增加了两倍。 Melioidosis代表了在低资源环境中迫切需要新疗法的肺炎和败血症的全球负担。我们已经确定了在黑梅利病中的Toll样受体5（TLR5）（TLR5）（TLR5）的关键作用。 TLR5缺乏效率加速了小鼠呼吸道感染的死亡，但是编码非功能受体的TLR5中常见的人类遗传变异与住院的混血症患者的生存率显着改善有关。该变体还与刺激血液的促炎细胞因子对假单胞菌的较低促炎性细胞因子反应有关。尽管唯一已知的TLR5配体是鞭毛蛋白，但遗传变体载体中的细胞因子反应降低与假单胞菌鞭毛蛋白芽孢杆菌无关，并且也观察到对假芽孢杆菌脂多糖糖糖（TLR4）tlr4激动剂的响应。这些有趣的初步遗传数据需要进一步研究TLR5遗传变异和鞭毛蛋白-TLR5轴对Melioidosis的影响的基础机制。对比的鼠和人类表型强调了在人类中进行转化科学的重要性。我们假设对这种受TLR5调节但独立于鞭毛蛋白感应的肺部效果生物的宿主炎症反应过多，这导致了梅尔塞迪病患者的器官功能障碍和死亡。我们将利用PI的转化混血症研究计划，并与泰国研究者的稳健合作以三种相关方式检验该假设：1）确定TLR5遗传变异是否与钝性的先天免疫激活相关，炎症反应减少，并改善了在糖浆病患者中的临床结果，2） 3）确定在假发芽孢杆菌感染中由TLR5遗传变异介导的差异信号传导是否与鞭毛蛋白传感无关。对TLR5在黑梅利病中的更好理解将增加治疗干预措施的潜力，并对全球肺炎和败血症的其他病因产生后果。

项目成果

Evaluation of antigen-detecting and antibody-detecting diagnostic test combinations for diagnosing melioidosis.

• DOI: 10.1371/journal.pntd.0009840
• 发表时间: 2021-11
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Amornchai P;Hantrakun V;Wongsuvan G;Wuthiekanun V;Wongratanacheewin S;Teparrakkul P;West TE;AuCoin DP;Day NPJ;Brett PJ;Burtnick MN;Chantratitra N;Limmathurotsakul D
• 通讯作者: Limmathurotsakul D

Sensitivity and specificity of a lateral flow immunoassay (LFI) in serum samples for diagnosis of melioidosis.

• DOI: 10.1093/trstmh/try099
• 发表时间: 2018-12-01
• 期刊: Transactions of the Royal Society of Tropical Medicine and Hygiene
• 影响因子: 2.2
• 作者: Wongsuvan G;Hantrakun V;Teparrukkul P;Imwong M;West TE;Wuthiekanun V;Day NPJ;AuCoin D;Limmathurotsakul D
• 通讯作者: Limmathurotsakul D

Management and outcomes of severe dengue patients presenting with sepsis in a tropical country.

• DOI: 10.1371/journal.pone.0176233
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Teparrukkul P;Hantrakun V;Day NPJ;West TE;Limmathurotsakul D
• 通讯作者: Limmathurotsakul D

Effectiveness of a sepsis programme in a resource-limited setting: a retrospective analysis of data of a prospective observational study (Ubon-sepsis).

• DOI: 10.1136/bmjopen-2020-041022
• 发表时间: 2021-02-18
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Booraphun S;Hantrakun V;Siriboon S;Boonsri C;Poomthong P;Singkaew BO;Wasombat O;Chamnan P;Champunot R;Rudd K;Day NPJ;Dondorp AM;Teparrukkul P;West TE;Limmathurotsakul D
• 通讯作者: Limmathurotsakul D

TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis.

• DOI: 10.1016/j.cmi.2016.08.028
• 发表时间: 2017-01
• 期刊: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
• 作者: Chantratita N;Tandhavanant S;Seal S;Wikraiphat C;Wongsuvan G;Ariyaprasert P;Suntornsut P;Teerawattanasook N;Jutrakul Y;Srisurat N;Chaimanee P;Mahavanakul W;Srisamang P;Phiphitaporn S;Mokchai M;Anukunananchai J;Wongratanacheewin S;Chetchotisakd P;Emond MJ;Peacock SJ;West TE
• 通讯作者: West TE