Sexually Transmitted Infections & Antimicrobial Peptides

性传播感染

• 批准号: 7151196
• 负责人: William Maurice Shafer
• 金额: $ 32.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151196
• 关键词: Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Appearance; Appendix; Bacteria; Biological Assay; Biological Models; Chemicals; Chlamydia trachomatis; Class; Cultured Cells; Development; Disease; Drug Efflux; Engineering; Epithelial Cells; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genital system; Genitourinary system; Goals; Health; Hemophilus ducreyi; Host Defense; Human; Hydrophobicity; In Vitro; Incidence; Infection; Inflammation; Invaded; Knowledge; Laboratories; Lactobacillus; Lesion; Liquid substance; Local Microbicides; Manuscripts; Mediator of activation protein; Microarray Analysis; Microbe; Modeling; Molecular Genetics; Mus; Mutagenesis; Mutation; Natural Immunity; Neisseria gonorrhoeae; Numbers; Oryctolagus cuniculus; Pattern; Peptides; Physiological Processes; Population; Predisposition; Prevention; Procedures; Production; Property; Recording of previous events; Resistance; Resistance development; Sexually Transmitted Diseases; Site; Skin; Stress; Surface; Syphilis; System; Techniques; Technology; Testing; Toxic effect; Treponema pallidum; Trichomonas vaginalis; Vagina; Variant; Woman; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; bactericide; chemical property; design; efflux pump; experience; in vivo; insight; interest; keratinocyte; killings; medical complication; member; microbial; neutrophil; novel; novel strategies; pathogen; research study; response; synthetic peptide; vaginal fluid

DESCRIPTION (provided by applicant): The incidence of sexually transmitted infections (STI) continues to be a global health problem. New and novel strategies are needed to reduce the incidence of STI, particularly in women as they often suffer from severe medical complications as a result of such infections. Our long-term goal is to understand the mechanisms of the innate host defense system that functions at mucosal surfaces in response to Neisseria gonorrhoeae. Antimicrobial peptides (AP) produced by phagocytic and epithelial cells are now recognized as important mediators of innate immunity. Due to their potent activity in vitro, we hypothesize that they could be engineered as topical microbicides for use in the prevention of STI. Towards that end, we are interested in how these peptides exert antigonococcal activity in vitro and how gonococci might subvert their antibiotic-like action through genetic and physiologic processes. The human AP termed LL-37 has been shown by us to exert potent action in vitro against N. gonorrhoeae and can block infection by Treponema pallidum in a rabbit skin lesion model. We have recently engineered truncated versions of LL-37 that maintain antigonococcal activity in vitro without killing lactobacilli, which are important members of the vaginal normal flora. In order to understand how LL-37 contributes to innate immunity during STI, we will design nontoxic variants of LL-37 that have enhanced capacities to kill bacterial pathogens (N. gonorrhoeae, Haemophilus ducreyi, T. pallidum and Chlamydia trachomatis) in vitro and in vivo but remain inactive against lactobacilli (Specific Aim 1). As is the case with other antibiotics, it is likely that bacterial pathogens can develop mechanisms to resist the action of AP. We will use the gonococcus as a model STI pathogen to examine this issue in order to identify the genes that may endow bacteria with the ability to constitutively (Specific Aim 2) or inducibly (Specific Aim 3) resist the action of LL-37.We will use transposon mutagenesis techniques in Specific Aim 2 and the micro array technology in Specific Aim 3 to identify these determinants. The results from our studies should generate novel compounds that could be used as topical microbicides to block STI, provide a better understanding of innate immunity at the genital mucosal surface during STI and result in important insights regarding bacterial responses to AP in vivo.

描述（由申请人提供）：性传播感染（STI）的发病率仍然是一个全球性的健康问题。需要新的策略来减少性传播感染的发病率，特别是女性，因为她们经常因此类感染而遭受严重的医疗并发症。我们的长期目标是了解在粘膜表面响应淋病奈瑟菌的先天宿主防御系统的机制。由吞噬细胞和上皮细胞产生的抗菌肽（AP）现在被认为是先天免疫的重要介质。由于它们在体外的有效活性，我们假设它们可以被设计为局部杀微生物剂，用于预防性传播感染。为此，我们对这些肽如何在体外发挥抗淋球菌活性以及淋球菌如何通过遗传和生理过程破坏其抗生素样作用感兴趣。我们已证明，称为 LL-37 的人类 AP 在体外对淋病奈瑟菌具有有效作用，并且可以在兔子皮肤损伤模型中阻断梅毒螺旋体的感染。我们最近设计了 LL-37 的截短版本，可在体外保持抗淋球菌活性，而不杀死乳酸杆菌，而乳酸杆菌是阴道正常菌群的重要成员。为了了解 LL-37 如何在性传播感染期间促进先天免疫，我们将设计 LL-37 的无毒变体，这些变体具有增强的体外杀死细菌病原体（淋病奈瑟菌、杜克雷嗜血杆菌、梅毒螺旋体和沙眼衣原体）的能力，在体内但对乳酸杆菌保持非活性（具体目标 1）。与其他抗生素的情况一样，细菌病原体可能会形成抵抗 AP 作用的机制。我们将使用淋球菌作为 STI 病原体模型来研究这个问题，以确定可能赋予细菌组成性（具体目标 2）或诱导性（具体目标 3）抵抗 LL-37 作用的能力的基因。我们将使用Specific Aim 2中的转座子诱变技术和Specific Aim 3中的微阵列技术来识别这些决定因素。我们的研究结果应该产生可用作局部杀微生物剂来阻断 STI 的新型化合物，更好地了解 STI 期间生殖器粘膜表面的先天免疫，并得出有关体内细菌对 AP 反应的重要见解。