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Pathogensis of Chlamydial Infection

衣原体感染的发病机制

基本信息

批准号：
10692060
负责人：
HARLAN D CALDWELL
金额：
$ 113.58万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10692060
关键词：
Affect Antibiotic Therapy Attenuated Vaccines Cessation of life Chlamydia Chlamydia Infections Chlamydia trachomatis Disease Ectopic Pregnancy Epithelial Cells Female Female genitalia Fibrinogen Functional disorder Future Gene Proteins Goals Host Defense Host Defense Mechanism Immune response Immunity Infection Inflammatory Interleukin-1 beta Investigation Lipoproteins Logic Mediating Membrane Membrane Proteins Modeling Mus Mutation Myelogenous Natural Immunity Pathogenicity Pelvic Inflammatory Disease Persons Pharmacotherapy Plasmids Prevention Process Public Health Research Sexually Transmitted Diseases Signal Transduction TLR2 gene Testing Trachoma Uterus Vaccines Virulence Factors Woman Work antimicrobial peptide base cell killing chronic infection design diagnostic screening health management immunopathology inhibitor mouse model neutrophil prevent reproductive tract tubal infertility urogenital tract

项目摘要

Chlamydia trachomatis infection of oculogenital epithelial cells causes blinding trachoma and sexually transmitted disease (STD); diseases that affect hundreds of millions of people world-wide. Infection of women has serious post-infection sequalae such as pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. A pathognomonic feature of these diseases is the inability of the host to generate an adequate protective immune response resulting in multiple episodes of re-infection or persistent infection that leads to damaging inflammatory disease of unknown pathophysiology. Current public health management of trachoma and STD is based on mass drug treatment or aggressive diagnostic screening and antibiotic treatment; respectively, that unfortunately have been largely ineffective. Effective control of trachoma and chlamydial STD requires a vaccine. The overall goal of our work is to understand the pathogenic mechanisms by which chlamydia evade host defenses that allow for the establishment of chronic infection and damaging inflammatory disease. Our logic is that a better understanding of the pathobiology of chlamydial infection and disease will be important to the design of new effective vaccines for the prevention of trachoma and STD. To this end, we have used a female mouse model of urogenital tract infection and focused our investigations on the study of two chlamydial virulence factors; (i) the C. trachomatis plasmid, and (ii) the C. trachomatis inclusion membrane protein CT135. We found the plasmid gene protein Pgp3 is required to establish persistent infection of the mouse female genital tract. We further identified the pathogenic mechanism of Pgp3 as an inhibitor of innate immunity anti-microbial peptides. We found that CT135 is essential for establishing continuous infection of uterine epithelial cells by killing luminal neutrophils by activating the NLRP3 inflammosome. CT135 was shown to function in inflammosome activation by exporting chlamydial outer membrane lipoprotein fragments generated during abortive chlamydial infection of neutrophils. Exported chlamydial lipoprotein fragments bound inclusion membrane associated TLR2 resulting in MyD88 signaling and activation of the NLRP3 inflammosome. This processes resulted in neutrophil death and secretion of IL1-beta. We conclude from these findings that CT135 functions to evade neutrophil host defense. Interestingly, this host defense mechanism conjointly drives genital tract myeloid mediated immunopathology. Future studies will design C. trachomatis vaccine strains that have been genetically modified to mutationally inactive CT135 and cured of the plasmid. These strains will be tested as live-attenuated vaccines to prevent chlamydial STD using the female mouse genital tract model.

眼生殖器上皮细胞的沙眼衣原体感染导致致盲性沙眼和性传播疾病（STD）;这些疾病影响全世界数亿人。女性感染后有严重的感染后遗症，如盆腔炎、输卵管因素不孕、宫外孕等。这些疾病的一个特征是宿主不能产生足够的保护性免疫应答，导致多次再感染或持续感染，从而导致病理生理学未知的破坏性炎症性疾病。目前对沙眼和性病的公共卫生管理分别基于大规模药物治疗或积极的诊断筛查和抗生素治疗;不幸的是，这在很大程度上无效。有效控制沙眼和衣原体性传播疾病需要疫苗。我们工作的总体目标是了解衣原体逃避宿主防御的致病机制，从而建立慢性感染和破坏性炎症疾病。我们的逻辑是，更好地了解衣原体感染和疾病的病理生物学将是重要的设计新的有效的疫苗，用于预防沙眼和性病。为此，我们使用了一种雌性小鼠泌尿生殖道感染模型，并将我们的调查集中在两个衣原体毒力因子的研究上：（i）衣原体毒力因子;沙眼衣原体质粒，和（ii）C.沙眼包涵体膜蛋白CT 135。我们发现质粒基因蛋白Pgp 3是建立小鼠雌性生殖道持续感染所必需的。我们进一步确定了Pgp 3作为先天免疫抗菌肽抑制剂的致病机制。我们发现CT 135通过激活NLRP 3炎性小体杀死管腔中性粒细胞，对建立子宫上皮细胞的持续感染至关重要。 CT 135被证明在炎性小体激活中起作用，通过输出中性粒细胞的衣原体感染失败期间产生的衣原体外膜脂蛋白片段。输出的衣原体脂蛋白片段结合包涵体膜相关的TLR 2，导致MyD 88信号传导和NLRP 3炎性小体的活化。该过程导致中性粒细胞死亡和IL 1-β的分泌。我们从这些发现中得出结论，CT 135的功能，以逃避嗜中性粒细胞宿主防御。有趣的是，这种宿主防御机制共同驱动生殖道骨髓介导的免疫病理学。未来的研究将设计C.沙眼疫苗株已被遗传修饰为突变失活的CT 135并消除了质粒。这些菌株将作为减毒活疫苗进行检测，以使用雌性小鼠生殖道模型预防衣原体STD。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Innate immunity is sufficient for the clearance of Chlamydia trachomatis from the female mouse genital tract.

DOI：
10.1111/2049-632x.12164
发表时间：
2014-10
期刊：
Pathogens and disease
影响因子：
3.3
作者：
Sturdevant GL;Caldwell HD
通讯作者：
Caldwell HD

Infectivity of urogenital Chlamydia trachomatis plasmid-deficient, CT135-null, and double-deficient strains in female mice.

DOI：
10.1111/2049-632x.12121
发表时间：
2014-06
期刊：
Pathogens and disease
影响因子：
3.3
作者：
Sturdevant GL;Zhou B;Carlson JH;Whitmire WM;Song L;Caldwell HD
通讯作者：
Caldwell HD

Fluorometric high-throughput assay for measuring chlamydial neutralizing antibody.

用于测量衣原体中和抗体的荧光高通量测定。

DOI：
10.1128/cvi.00460-12
发表时间：
2012
期刊：
Clinical and vaccine immunology : CVI
影响因子：
0
作者：
Southern,Timothy;Bess,Leah;Harmon,Jillian;Taylor,Lacey;Caldwell,Harlan
通讯作者：
Caldwell,Harlan

Plasmid-mediated transformation tropism of chlamydial biovars.

DOI：
10.1111/2049-632x.12104
发表时间：
2014-03
期刊：
Pathogens and disease
影响因子：
3.3
作者：
Song L;Carlson JH;Zhou B;Virtaneva K;Whitmire WM;Sturdevant GL;Porcella SF;McClarty G;Caldwell HD
通讯作者：
Caldwell HD

Antibody signature of spontaneous clearance of Chlamydia trachomatis ocular infection and partial resistance against re-challenge in a nonhuman primate trachoma model.

DOI：
10.1371/journal.pntd.0002248
发表时间：
2013
期刊：
PLoS neglected tropical diseases
影响因子：
3.8
作者：
Kari L;Bakios LE;Goheen MM;Bess LN;Watkins HS;Southern TR;Song L;Whitmire WM;Olivares-Zavaleta N;Caldwell HD
通讯作者：
Caldwell HD