Vaccination to protect against infection of the female reproductive tract

Infection of the female genital tract can result in serious morbidities and mortalities from reproductive disability, pelvic inflammatory disease and cancer, to impacts on the fetus, such as infant blindness. While therapeutic agents are available, frequent testing and treatment is required to prevent the occurrence of the severe disease sequelae. Hence, sexually transmitted infections remain a major public health burden with ongoing social and economic barriers to prevention and treatment. Unfortunately, while there are two success stories in the development of vaccines to protect against HPV infection of the female reproductive tract, many serious infectious agents impacting on the female reproductive tract still have no vaccines available. Vaccination to prevent infection of the female reproductive tract is an inherently difficult target, with many impacting factors, such as appropriate vaccination strategies/mechanisms to induce a suitable protective response locally in the genital tract, variation in the local immune responses due to the hormonal cycle, selection of vaccine antigen(s) that confers effective protection against multiple variants of a single pathogen (e.g., the different serovars of Chlamydia trachomatis) and timing of the vaccine administration prior to infection exposure. Despite these difficulties, there are numerous ongoing efforts to develop effective vaccines against these infectious agents and it is likely that this important human health field will see further major developments in the next 5 years.     

The Combination of the Gastrointestinal Integrin (α4β7) and Selectin Ligand Enhances T-Cell Migration to the Reproductive Tract During Infection with Chlamydia trachomatis

Problem  Chlamydia trachomatis causes sexually transmitted infection and reproductive dysfunction worldwide. Identifying a population of endocervical T-cells to target in vaccine development is likely to enhance efficacy of a vaccine and reduce reproductive tract dysfunction.
Method of study  Endocervical samples were obtained from young women and flow cytometric analysis was used to identify lymphocytes that appeared in the genital tract in response to sexually transmitted bacterial infections caused by C. trachomatis.
Results  Increased numbers of α4β7+CLA+ memory T-cells, a unique T-cell phenotype, were found in the endocervix of human female subjects infected with C. trachomatis .
Conclusion A unique population of memory T lymphocytes expressing both α4β7 and CLA gain access to reproductive tract tissues during a sexually transmitted infection with C. trachomatis and should be considered in development of vaccines against sexually transmitted infections.     

Regulation of surfactant protein D in the mouse female reproductive tract in vivo

Surfactant protein D (SP-D) plays a role in innate immunity in the lung and is expressed at many other mucosal surfaces throughout the human body. In this study, we show that SP-D mRNA and protein are present in the murine female reproductive tract; i.e. in the vagina, cervix, uterus and oviduct. SP-D protein is primarily localized to epithelial cells lining the genital tract and is also present in secretory material within the lumen of the uterus and cervix. The levels of SP-D mRNA in the uterus vary by a factor of 10 during the estrous cycle with peak levels present at estrus and the lowest levels at diestrus. In contrast, SP-D mRNA levels in the lung do not change during the estrous cycle. Since SP-D is an innate host defense protein present in the mouse reproductive tract, we studied the influence of infection on SP-D levels in vivo. We found that Chlamydia muridarum infection caused an increase in the SP-D protein content of reproductive tract epithelial cells. These data are suggestive that SP-D may play a role in innate immunity in the female reproductive tract in vivo.     

VAGINAL IMMUNITY IN THE HSV-2 MOUSE MODEL

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract. Efforts to develop vaccines to protect women against this and other sexually transmitted pathogens would be facilitated by a better understanding of the immune mechanisms that protect the female reproductive tract against such infections. Such information would be invaluable in developing vaccine strategies to promote the type and magnitude of immune responses in the genital tract that would effectively protect against infection. This review focuses on recent studies using a progestin-treated adult mouse model to explore mucosal immunity to HSV-2 in the vagina. Evidence indicating a major role for both humoral and T cell immunity is presented.     

Vaginal immunity in the HSV-2 mouse model

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that infects the genital tract. Efforts to develop vaccines to protect women against this and other sexually transmitted pathogens would be facilitated by a better understanding of the immune mechanisms that protect the female reproductive tract against such infections. Such information would be invaluable in developing vaccine strategies to promote the type and magnitude of immune responses in the genital tract that would effectively protect against infection. This review focuses on recent studies using a progestin-treated adult mouse model to explore mucosal immunity to HSV-2 in the vagina. Evidence indicating a major role for both humoral and T cell immunity is presented.     

Toll-Like Receptors, Inflammation and Tumor in the Human Female Reproductive Tract

Abstract  Toll-like receptors are an important family of pattern recognition receptors. They recognize microbial conserved components and trigger protective responses to the invading pathogens, which constitute a major part of the innate immune system. Toll-like receptors are mainly expressed in immune cells. The current evidences demonstrate that Toll-like receptors are present in some epithelial cells and epithelium derived tumor cells. The expression of Toll-like receptors in these cells is related to infection and inflammation, and tumor progression as well. Genital mucosal epithelium is the first line in defense of microorganism invasion in the female reproductive tract. Toll-like receptors expressed in the genital tract have been implicated in many aspects of reproductive physiology and pathology in the female. In the current review, we will focus on the expression of Toll-like receptors in the female genital mucosa and its association with anti-infection immunity and tumorigenesis.     

REVIEW ARTICLE: Chlamydia trachomatis,a Hidden Epidemic: Effects on Female Reproduction and Options for Treatment

Citation Carey AJ, Beagley KW. Chlamydia trachomatis, a hidden epidemic: effects on the female reproduction and options for treatment. Am J Reprod Immunol 2010 The number of genital tract Chlamydia trachomatis infections is steadily increasing worldwide, with approximately 50–70% of infections asymptomatic. There is currently no uniform screening practice, current antibiotic treatment has failed to prevent the increased incidence, and there is no vaccine available. We examined studies on the epidemiology of C. trachomatis infections, the effects infections have on the female reproductive tract and subsequent reproductive health and what measures are being taken to reduce these problems. Undetected or multiple infections in women can lead to the development of severe reproductive sequelae, including pelvic inflammatory disease and tubal infertility. There are two possible paradigms of chlamydial pathogenesis, the cellular and immunological paradigms. While many vaccine candidates are being extensively tested in animal models, they are still years from clinical trials. With no vaccine available and antibiotic treatment unable to halt the increased incidence, infection rates will continue to increase and cause a significant burden on health care systems.     

妊娠合并生殖道感染

近几年来,妊娠期合并生殖道感染有上升趋势,引起感染的病原体类型也发生了变化,沙眼衣原体感染有取代淋球菌感染的趋势。妇女妊娠期生殖道感染除影响孕妇健康外,还可通过垂直传播或经宫颈感染胎儿,引起自然流产、胎膜早破、死胎、死产、胎儿宫内发育迟缓、胎儿低体重、胎儿畸形等,造成一系列不良妊娠结局。由于妊娠期妇女处于免疫抑制状态,其生殖道感染处于隐性状态,常无明显临床症状,直至造成严重后果才被发现,所以必须定期检查,做到早诊断、早发现、早治疗。现将妊娠合并生殖道感染的途径、病原种类及其对妊娠结局的影响作一综述如下。     

女性生殖道黏膜免疫进展

黏膜免疫是抵御细菌、病毒等病原体侵入机体的第一道防线。女性生殖道黏膜免疫通过固有免疫和适应性免疫不仅可抵抗致病菌的入侵,还有助于成功受精及妊娠,从而维持女性生殖健康。女性生殖道固有免疫系统包括黏膜上皮的机械屏障、共生菌的微生物屏障、固有免疫细胞及其受体的免疫屏障,适应性免疫包括B细胞介导的体液免疫及T细胞介导的细胞免疫。女性生殖道黏膜免疫不仅参与局部炎症,还可能具有抗肿瘤免疫应答的作用。此外,女性生殖道黏膜免疫受性激素的调节,从而有利于维持局部微环境的稳态。本文就近年有关女性生殖道黏膜免疫的研究进展进行总结。     

Subclinical chlamydial infection of the female mouse genital tract generates a potent protective immune response: implications for development of live attenuated chlamydial vaccine strains

Chlamydia trachomatis is a major cause of sexually transmitted disease (STD) for which a vaccine is needed. CD4(+) T-helper type 1 (Th1) cell-mediated immunity is an important component of protective immunity against murine chlamydial genital infection. Conventional vaccine approaches have not proven effective in eliciting chlamydial-specific CD4 Th1 immunity at the genital mucosa. Thus, it is possible that the development of a highly efficacious vaccine against genital infection will depend on the generation of a live attenuated C. trachomatis vaccine. Attenuated strains of C. trachomatis do not exist, so their potential utility as vaccines cannot be tested in animal models of infection. We have developed a surrogate model to study the effect of chlamydial attenuation on infection and immunity of the female genital tract by treating mice with a subchlamydiacidal concentration of oxytetracycline following vaginal infection. Compared to untreated control mice, antibiotic-treated mice shed significantly fewer infectious organisms (3 log(10)) from the cervico-vagina, produced a minimal inflammatory response in urogenital tissue, and did not experience infection-related sequelae. Antibiotic-treated mice generated levels of chlamydia-specific antibody and cell-mediated immunity equivalent to those of control mice. Importantly, antibiotic-treated mice were found to be as immune as control untreated mice when rechallenged vaginally. These findings demonstrate that subclinical chlamydial infection of the murine female genital tract is sufficient to stimulate a potent protective immune response. They also present indirect evidence supporting the possible use of live attenuated chlamydial organisms in the development of vaccines against chlamydial STDs.     

Mucin expression and function in the female reproductive tract

Reproductive tract epithelia are characterized by the presence of a thick, apical glycocalyx. This glycoprotein coat is drastically reduced in the uterus of many species during the time of embryo implantation. Recent studies indicate that mucin glycoproteins constitute a large proportion of the apical glycocalyx. One of these mucins, Muc-1, has particularly important functions at the luminal surface of the uterus and other female reproductive tract tissues. Muc-1 appears to play a dominant role in maintaining a functionally non-receptive uterine surface with regard to blastocyst attachment. Conversion to a receptive uterine state is brought about by the concerted actions of ovarian steroid hormones that in several species also strongly modulate Muc-1 protein and mRNA expression. Muc-1 also appears to serve a general function in protecting reproductive tract mucosa since Muc-1 null mice are particularly prone to bacterial infection. Collectively, these studies indicate that mucins, including Muc-1, play important barrier roles in reproductive processes and protection from bacterial pathogenesis in the female reproductive tract.     

宫颈癌患者生殖道感染的研究进展

宫颈癌是威胁女性身心健康的最常见恶性肿瘤之一。近年来,关于宫颈癌的相关危险因素一直是医学领域研究的热点方向,且宫颈癌与生殖道感染的相关性研究逐渐增多。目前研究表明生殖道感染可能是宫颈癌发生的潜在危险因素,同时阴道微生态失衡在生殖道感染中发挥重要作用。阴道微环境在外界和机体环境中保持一定的动态平衡,当这种平衡遭到破坏,各种生殖道感染就可能发生。生殖道感染与宫颈癌息息相关,本文就宫颈癌与常见的生殖道感染及生殖道感染的微生态状况进行综述。     

Tolerance and Protection against Infection in the Genital Tract

The genital tract is a unique immunological environment that must support the reproductive function and resist infection. Particularly in the female tract, immunoregulatory and immunosuppressive activities that permit the growth of the fetus create an environment that can readily be exploited by microbes that have become well-adapted to this location. Cellular and molecular mediators of immune responses differ from those found at other mucosal surfaces. Mechanisms of immune response induction and delivery, as well as immune effector functions at the genital mucosae need to be considered in the development of vaccines against infections of the genital tract.     

Immunization with a replication-defective herpes simplex virus 2 mutant reduces herpes simplex virus 1 infection and prevents ocular disease

Ocular infections with herpes simplex virus 1 can lead to corneal scarring and blindness, with herpes keratitis being the major infectious cause of blindness. There is currently no clinically approved vaccine and nearly all developmental vaccines are targeted against HSV-2 and genital herpes. We tested the ability of an HSV-2 replication-defective virus, a genital herpes vaccine candidate, to protect against HSV-1 corneal infection. Immunization with HSV-2 dl5-29 reduced viral replication in the cornea, prevented ocular disease and reduced latent infection by the HSV-1 strain. Therefore, this HSV-2 replication-defective mutant strain may have applications for prevention of herpes keratitis and genital herpes due to HSV-1 infection.     

Characterization of Toll-like receptors in the female reproductive tract in humans

BACKGROUND: Rapid innate immune defences against infection involve the recognition of invading pathogens by specific pattern recognition receptors recently attributed to the family of Toll-like receptors (TLR). Little is known about the in vivo protein expression or distribution of TLR in the female reproductive tract in humans. It is likely that TLR distribution in the female reproductive tract reflects the immunological tolerance to the commensal organisms in lower parts of the tract (vagina, ectocervix and, partially, endocervix) and the intolerance to commensal microbial flora in the upper tract (the uterus and uterine tubes). METHODS: Using immunohistochemistry techniques, distribution of TLR1-6 was studied in surgical sections from the vagina, ecto- and endocervix, endometrium and uterine tubes, obtained from patients undergoing abdominal hysterectomy for benign gynaecological conditions. RESULTS: TLR1, 2, 3, 5 and 6 were present in the epithelia of different regions of female reproductive tract. However, TLR4 was only present in the endocervix, endometrium and uterine tubes and absent in vagina and ectocervix. In addition, a secretory form of TLR4 seems to be produced by the endocervical glands. CONCLUSION: TLR4 may play an important role in modulation of immunological tolerance in the lower parts of the female reproductive tract, and in host defence against ascending infection.     

Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice.

Attenuated strains of Salmonella are attractive live vaccine candidates for eliciting mucosal as well as systemic immune responses. The ability to induce immune responses in the reproductive tract may be critical for the effectiveness of a prophylactic vaccine against genital human papillomaviruses (HPV), which are important etiologic agents in the development of cervical cancer. To examine the potential of a live Salmonella-based vaccine to prevent genital HPV infection, the L1 major capsid protein from HPV type 16 (HPV16) was constitutively expressed in the PhoPc strain of Salmonella typhimurium. As demonstrated by electron microscopy, the L1 protein expressed in these bacteria assembled into virus-like particles (VLPs) that resemble authentic papillomavirus virions. This is the first demonstration that papillomavirus VLPs can self-assemble in prokaryotes. BALB/c mice were immunized with the HPV16 L1 recombinant PhoPc strain by the oral and nasal routes. Despite a low stability of the L1-expressing plasmid in vivo, a double nasal immunization was effective in inducing L1-specific serum antibodies that recognized mainly native, but not disassembled, VLPs. These antibodies effectively neutralized HPV16 pseudotyped virions in an in vitro infectivity assay. Conformationally dependent anti-VLP immunoglobulin A (IgA) and IgG were also detected in oral and vaginal secretions, indicating that potentially protective antibody responses were elicited at mucosal sites. Recombinant attenuated Salmonella expressing HPV capsids may represent a promising vaccine candidate against genital HPV infection.     

Current status of veterinary vaccines

The major goals of veterinary vaccines are to improve the health and welfare of companion animals, increase production of livestock in a cost-effective manner, and prevent animal-to-human transmission from both domestic animals and wildlife. These diverse aims have led to different approaches to the development of veterinary vaccines from crude but effective whole-pathogen preparations to molecularly defined subunit vaccines, genetically engineered organisms or chimeras, vectored antigen formulations, and naked DNA injections. The final successful outcome of vaccine research and development is the generation of a product that will be available in the marketplace or that will be used in the field to achieve desired outcomes. As detailed in this review, successful veterinary vaccines have been produced against viral, bacterial, protozoal, and multicellular pathogens, which in many ways have led the field in the application and adaptation of novel technologies. These veterinary vaccines have had, and continue to have, a major impact not only on animal health and production but also on human health through increasing safe food supplies and preventing animal-to-human transmission of infectious diseases. The continued interaction between animals and human researchers and health professionals will be of major importance for adapting new technologies, providing animal models of disease, and confronting new and emerging infectious diseases.     

Surfactant protein D is present in the human female reproductive tract and inhibits Chlamydia trachomatis infection

Surfactant protein D (SP-D) is a lung collectin involved in innate host defence mechanisms in the lung. SP-D is also expressed at other mucosal sites throughout the human body. In the present study, we show that SP-D mRNA and protein are expressed in the human female reproductive tract. SP-D protein was localized in the apical portion of the reproductive epithelial cells. We also demonstrate that endometrial and endocervical cell lines and primary endocervical cells in culture produce SP-D mRNA and protein. Chlamydia trachomatis is an intracellular pathogen that infects the female reproductive tract, primarily the cervix, and is responsible for the most prevalent infectious disease in the USA. Untreated chlamydial infections of the female reproductive tract often result in sterility of the infected woman. Since SP-D protein is produced in cervical glands, we examined the effect of SP-D on chlamydial infection of cervical epithelial cells in vitro. We found that SP-D protein inhibits the infection of HeLa cells (an endocervical epithelial cell line) by C. trachomatis in a dose-dependent manner. We further demonstrate that the SP-D lectin-binding domain is involved in inhibiting infection of HeLa cells by Chlamydia. In conclusion, we detected SP-D in the female reproductive tract and determined that one of the functions of the SP-D protein may be to protect cervical epithelial cells from infection by C. trachomatis.     

Developing HPV virus-like particle vaccines to prevent cervical cancer: a progress report.

BACKGROUND: the knowledge that sexually transmitted infection with one of a limited number of human papillomaviruses (HPVs) is a central cause of almost all cervical cancers affords the opportunity to prevent this common cancer through anti-viral vaccination. OBJECTIVE: the spectacular success of vaccines in preventing several other viral diseases offers hope that immunoprophylaxis against the relevant HPVs could lead to a major reduction in cervical cancer incidence. RESULTS AND CONCLUSION: the results of preclinical studies and early phase clinical trials of virus-like particle (VLP) based subunit vaccines have been very encouraging. However, unique aspects of papillomavirus biology and genital tract infections, and the lack of sexual a transmission model for papillomavirus, make it far from certain that effective prophylactic vaccination against genital HPV infection will be easily achieved. Future clinical efficacy trials will likely test the hypothesis that parenteral injection of VLPs can induce antibody mediated and type specific protection against genital tract HPV infection and subsequent development of premalignant neoplastic disease.     

丙型肝炎疫苗的研究进展

丙型肝炎是由丙型肝炎病毒(HepatitisCvirus,HCV)感染而引起的严重威胁人类健康的传染病,目前还没有研制成功有效的预防性疫苗,HCV基因组的高度变异及缺乏易感动物模型一直是妨碍丙肝疫苗发展的瓶颈。随着对HCV免疫清除机制的逐渐认识,诱导交叉反应性中和抗体和细胞免疫应答已成为丙肝疫苗研究的基本方向。本文概述了免疫应答在控制HCV感染过程中的作用以及当前丙肝疫苗的研究策略,并分析了丙肝疫苗的发展前景。