Virulence-Associated Proteins of Pathogenic Leptospira Species

致病性钩端螺旋体的毒力相关蛋白

• 批准号: 7686045
• 负责人: James Matsunaga
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686045
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adherence; Adhesions; Affect; Affinity; Afghanistan; Amino Acids; Animal Model; Animals; Antibody Formation; Antigens; Area; Attenuated; Bacteria; Bacterial Infections; Baltimore; Binding; Blood Tests; Cell Communication; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Communicable Diseases; Data; Detection; Diagnosis; Dialysis procedure; Disease; Effectiveness; Enzymes; Exposure to; Family; Fibronectins; Funding; HIV; Hamsters; Healthcare; Homelessness; Human; Immunoglobulin M; Immunoglobulins; Implant; Infection; Invaded; Kidney; Leptospira; Leptospira interrogans; Leptospirosis; Liver; Mammalian Cell; Mediating; Medical center; Membrane; Middle East; Military Personnel; Molecular; Neurologic Manifestations; Order Spirochaetales; Osmolar Concentration; Osmoregulation; Pathogenesis; Patients; Peptide Hydrolases; Physiological; Play; Populations at Risk; Poverty; Property; Protease Inhibitor; Proteins; Rattus; Recombinants; Regulation; Research; Risk; Rodent; Role; Serological; Site-Directed Mutagenesis; Staging; Symptoms; Testing; United States; Urine; Vaccination; Vaccines; Veterans; Virulence; Virulent; Zoonoses; base; clinically relevant; cost; deletion analysis; extracellular; flu; improved; inhibitor/antagonist; inner city; male; neglect; novel; patient population; prevent; public health relevance; tool

DESCRIPTION (provided by applicant): Clinical Relevance. Leptospirosis is a potentially fatal bacterial infection that is considered by the Centers for Disease Control to be the most widespread infectious disease that can be acquired from infected animals. Flu-like symptoms, often the only symptoms of early disease in leptospirosis, are characteristic of many infectious diseases, delaying diagnosis and treatment. Diagnosis is further hindered by the lack of a reliable blood test for acute leptospirosis. A safe and effective human leptospiral vaccine currently does not exist. Recent studies have demonstrated that the Lig proteins of Leptospira can serve as serologic antigens for detection of leptospiral infection in its early stages. Moreover, studies with hamsters, the standard animal model used in leptospirosis research, demonstrated that vaccination with the LigA protein prevented disease when the animals were later injected with Leptospira, although the bacteria were still able to colonize the kidneys. Our proposed studies of the binding properties of Lig proteins to human and rodent cells will allow us to rationally improve the effectiveness of the LigA vaccine, which may target the attachment activity of the Lig proteins. Novel treatments for leptospirosis can also be developed by identifying protease inhibitors of the leptospiral enzyme that causes LigA to be released from the bacteria thereby possibly facilitating spread of the bacteria throughout the body. Inhibitors of the same class are currently administered to patients infected with HIV to stall progression to AIDS. PUBLIC HEALTH RELEVANCE: Potential Impact on Veteran Health Care. Leptospirosis is a neglected disease of poverty in the United States. Urban residents are at particular risk for leptospirosis if homelessness results in exposure to urine of rats shedding Leptospira. One study found that 16% of Baltimore's inner city black males, an important component of the patient population served by VA medical centers. The Department of Veterans Affairs has identified leptospirosis as an important potential cause of illness for military personnel serving in many areas of the world, including Afghanistan and the Middle East. Ocular and neurologic manifestations of leptospirosis may not appear for several months to years following the initial exposure. For these reasons, there is an urgent need for new serodiagnostic tools to rapidly identify military personnel and veterans exposed to Leptospira. Additionally, a safe and effective low-cost vaccine may be beneficial for VA populations at risk for leptospirosis.

描述（由申请人提供）： 临床相关性。钩端螺旋体病是一种潜在致命的细菌感染，疾病控制中心认为它是可以从受感染动物身上获得的最广泛的传染病。流感样症状通常是钩端螺旋体病早期疾病的唯一症状，是许多传染病的特征，延误了诊断和治疗。由于缺乏针对急性钩端螺旋体病的可靠血液检测，诊断进一步受到阻碍。目前尚不存在安全有效的人类钩端螺旋体疫苗。最近的研究表明，钩端螺旋体的 Lig 蛋白可以作为钩端螺旋体感染早期检测的血清学抗原。此外，对仓鼠（钩端螺旋体病研究中使用的标准动物模型）的研究表明，当动物随后注射钩端螺旋体时，接种 LigA 蛋白疫苗可以预防疾病，尽管细菌仍然能够在肾脏中定殖。我们提出的关于Lig蛋白与人类和啮齿动物细胞的结合特性的研究将使我们能够合理地提高LigA疫苗的有效性，该疫苗可能针对Lig蛋白的附着活性。还可以通过鉴定钩端螺旋体酶的蛋白酶抑制剂来开发钩端螺旋体病的新疗法，该酶导致LigA从细菌中释放，从而可能促进细菌在全身的传播。目前，感染艾滋病毒的患者使用同类抑制剂来阻止艾滋病的进展。 公共卫生相关性： 对退伍军人医疗保健的潜在影响。钩端螺旋体病是美国一种被忽视的贫困疾病。如果城市居民无家可归导致接触排出钩端螺旋体的老鼠的尿液，那么城市居民患钩端螺旋体病的风险尤其高。一项研究发现，巴尔的摩内城区 16% 的黑人男性是退伍军人管理局医疗中心服务的患者群体的重要组成部分。美国退伍军人事务部已确定钩端螺旋体病是在世界许多地区（包括阿富汗和中东）服役的军事人员患病的一个重要潜在原因。初次接触钩端螺旋体病后数月至数年可能不会出现眼部和神经系统症状。由于这些原因，迫切需要新的血清诊断工具来快速识别暴露于钩端螺旋体的军事人员和退伍军人。此外，安全有效的低成本疫苗可能对有钩端螺旋体病风险的退伍军人事务部人群有益。