Sexually Transmitted Infections & Antimicrobial Peptides

性传播感染

• 批准号: 6985394
• 负责人: William Maurice Shafer
• 金额: $ 33.47万
• 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/6985394
• 关键词: Chlamydia trachomatis; Haemophilus ducreyi; Lactobacillus; Neisseria gonorrhoeae; Treponema pallidum; antibacterial agents; bactericidal immunity; drug design /synthesis /production; drug resistance; female; gonorrhea; laboratory mouse; laboratory rabbit; microarray technology; mucosal immunity; peptides; protein engineering; sexually transmitted diseases; topical drug application; transposon /insertion element

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）的发生率仍然是全球健康问题。需要新的和新颖的策略来减少STI的发生率，尤其是在女性中，因为她们通常由于这种感染而患有严重的医疗并发症。我们的长期目标是了解对淋巴结淋巴结淋巴结淋巴结在粘膜表面起作用的先天宿主防御系统的机制。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，我们假设它们可以用作局部菌心，以预防STI。为此，我们对这些肽在体外如何发挥抗癌活性以及淋球菌如何通过遗传和生理过程颠覆其类似抗生素的作用。我们已经证明，称为LL-37的人类AP在体外对淋病链球菌发挥有效的作用，并且可以在兔皮肤病变模型中通过treponema pallidum阻断感染。我们最近设计了LL-37的截短版本，这些版本在体外维持抗癌症活性而不杀死乳酸杆菌，这是阴道正常菌群的重要成员。为了了解LL-37在STI期间如何促进先天免疫力，我们将设计LL-37的无毒变体，这些变体具有增强的杀死细菌病原体的能力（N. gonorrhoeae，Haemophilus ducreyi，T。pallidum and pallidum and Chlamydia trolachomatis in Chamydia in Chamydia in Chamydia in Vivo）intro和特定的Activie（intro）。与其他抗生素一样，细菌病原体可能会发展出抗AP作用的机制。我们将使用淋球菌作为STI病原体来检查此问题，以识别可能具有组成型（特定目标2）或诱导性的能力（特定目的3）的基因（特定目标3）。我们将使用LL-37的作用。我们将使用特定的AIM中的特定目标2和Mictro ARINARE 2和MICRO ARNAY ARRAY TECHICES中的特定目标识别这些确定目标3。我们研究的结果应产生新的化合物，可以用作局部菌心来阻断性传播感染，更好地了解STI期间生殖器粘膜表面的先天免疫力，并导致有关对体内AP的细菌反应的重要见解。