Zugl.: Berlin, Humboldt-Univ., Diss., 2009

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 122-146).

Infections with the bacterial pathogen Chlamydia trachomatis are a critical public health problem. Chlamydia remains the number one cause of preventable blindness worldwide and the leading cause of bacterial sexually transmitted infections in the United States. In humans, repeat and persistent infections with Chlamydia result in severe inflammation. Inflammation in the conjunctiva can result in blindness, while inflammation in the genital tract can result in pelvic inflammatory disease, ectopic pregnancy or infertility. In order to curb the increasing incidence of Chlamydia infections worldwide it will be necessary to develop a protective vaccine that affords long-term protection and prevents pathologies. To better inform vaccine development we must understand the mechanisms that drive long-term immunity in the genital tract and elucidate critical interactions between Chlamydia and host cells to uncover potential mechanisms of immune evasion.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Chlamydia trachomatis (CT) is a pestilent infection affecting upwards of 90 million people worldwide. An efficacious vaccine is needed to control the morbidities and rising healthcare cost associated with genital CT infection. We have established that protection against chlamydia infection parallels with a high frequency of T helper Type 1 cells and the associated antibodies. The current study focuses on the induction of innate immune responses involved during Chlamydia infection by a Vibrio cholera ghost-based (VCG) vaccine vector. THP-1 cells were used for dose and kinetic experiments. HeLa cells were used for infectivity assays. Based on preliminary studies, we hypothesized that the induction of immune responses by a VCG-based vaccine involves multiple innate immune signaling. Multiplex assay was used to measure T helper Type I and Type II cytokine secretion by THP-1 monocytes (Mn) or macrophages (Mϕ). Immunostimulatory cytokine secretion was significant when both cell morphologies were pulsed with VCG or VCG/murine splenocytes. We concluded that this secretion was significant enough to compliment that which would be secreted when THP-1 cells are pulsed with Chlamydia elementary bodies alone, enhancing the innate immune response during infection. Cellular supernatants (conditioned media) containing Th1-type and Th2-type cytokines were used to culture Chlamydia-infected HeLa cell monolayers. Infected HeLa monolayers cultured in the conditioned media were significantly less infected (968 IFUs) versus HeLa monolayers cultured in Earle’s minimum essential media (16,486 IFUs; p<0.001). We concluded that factors contained in conditioned media prevent and/or significantly reduce infection by Chlamydia and the development of inclusion forming units.

The overall aim was to explore the experiences of sexual risk taking among Chlamydia Trachomatis positive (CT+), HIV positive (HIV+), and HIV tested young women and men. The specific aims were to explore, from a gender perspective, the course of events, the norms, considerations and emotions involved in sexual risk taking in CT+, explore the perception of sexual risk taking in HIV+ youth, and their understanding of why they caught HIV and look at how the Law of Communicable Diseases Act impacts their sexuality. Moreover, to investigate why young adults test for HIV, how they construct the HIV risk, and what implications testing has for them. 42 informants between 17-24 years of age were recruited from a youth clinic in Umeå and from three infection clinics for HIV patients in Sweden. In depth interviews and focus group interviews were tape-recorded, transcribed verbatim and analyzed according to a Grounded Theory approach. The finding revealed that behind sexual risk taking, there was a drive to go steady, where lust and trust guided if sex would take place. In one-night stands women were expected to be less forward compared with men. We found an uneven responsibility concerning condom use where men expected women to be "condom promoters". By catching CT, women experienced guilt, while men felt content through knowing "the source of contamination". Among the HIV+ youth, socio-cultural factors such as; lack of adult supervision, naivité, love, alcohol, drugs, the macho ideal and cultures of silence blinded the informants to the risks and made them vulnerable. By grouping narratives according to degree of consensus in sexual encounters, this demonstrated that sexual risks happened in a context of gendered power relations where the informants had varied agency. The Law of Communicable Diseases Act implied both support and burden for these HIV+ youth. A lot of responsibility was put on them and to be able to handle the infromation duty they tried to switch off lust, switch off the disease, or balance lust and obedience. Among the HIV tested youth, HIV was seen a distant threat. Many had event-driven reasons for testing for HIV; multiple partners being one. Risk zones, like bars were perceived to be a milieu that often was expected to include one-night stands. Responsibility for testing was a gendered issue; "natural" for women, while men rather escaped from responsibility and had a testing resistance. Receiving a "green card" confirmed healthiness and provided relief, and made the informants felt "clean". They could restart with new ambitious, including reconsidering risk. The findings can be used in public health and in health care sectors that work with young people. We present suggestions on how to decrease the spread of STIs: To implement how men could play an equal part in sexual and reproductive health. Promote general CT screening for men. Liberal HIV testing among both young women and men. Promote safer sex behaviour from the uninfected youth, especially focusing on men??. Consider the role of gender and social background in the context of risky behaviours. Give lots of positive rewards concerning HIV disclosure to diminish the risk for HIV transmission.

No description available.

Chlamydia, caused by the bacterium Chlamydia trachomatis, is one of the most important sexually-transmitted infections globally. In addition to accounting for millions of cases every year, the disease causes numerous irreversible complications such as chronic pelvic pain, infertility in females and pelvic inflammatory disease. This thesis presents a number of mathematical models, of the form of deterministic systems of non-linear differential equations, for gaining qualitative insight into the transmission dynamics and control of Chlamydia within an infected host (in vivo) and in a population. The models designed address numerous important issues relating to the transmission dynamics of Chlamydia trachomatis, such as the roles of immune response, sex structure, time delay (in modelling the latency period) and risk structure (i.e., risk of acquiring or transmitting infection). The in-host model is shown to have a globally-asymptotically stable Chlamydia-free equilibrium whenever a certain biological threshold is less than unity. It has a unique Chlamydia-present equilibrium when the threshold exceeds unity. Unlike the in-host model, the two-group (males and females) population-level model undergoes a backward bifurcation, where a stable disease-free equilibrium co-exists with one or more stable endemic equilibria when the associated reproduction number is less than unity. This phenomenon, which is shown to be caused by the re-infection of recovered individuals, makes the effort to eliminate the disease from the population more difficult. Extending the two-group model to incorporate risk structure shows that the backward bifurcation phenomenon persists even when recovered individuals do not acquire re-infection. In other words, it is shown that stratifying the sexually-active population in terms of risk of acquiring or transmitting infection guarantees the presence of backward bifurcation in the transmission dynamics of Chlamydia in a population. Finally, it is shown (via numerical simulations) that a future Chlamydia vaccine that boosts cell-mediated immune response will be more effective in curtailing Chlamydia burden in vivo than a vaccine that enhances humoral immune response. The population-level impact of various targeted treatment strategies, in controlling the spread of Chlamydia in a population, are compared. In particular, it is shown that the use of treatment could have positive or negative population-level impact (depending on the sign of a certain epidemiological threshold).

La chlamydiose génitale est une infection transmise sexuellement causée par la bactérie intracellulaire obligatoire Chlamydia trachomatis. Avec une incidence en constante augmentation depuis 1997, la chlamydiose génitale représente aujourd’hui la maladie à déclaration obligatoire la plus rapportée au Canada et correspond à 80% de l'ensemble des ITS diagnostiquées. Par contre, environ 15% des patients traités pour la chlamydiose génitale sont toujours infectés après la fin du traitement. Au-delà des réinfections possibles à la suite de contacts sexuels non-protégés avec un partenaire infecté, nous avons émis l’hypothèse que des causes bactériennes puissent être responsables des cas d'échec de traitement et d'infection persistante. Les travaux de recherches présentés dans ce mémoire ont donc eu pour objectifs de déterminer si la résistance à l’azithromycine, la charge bactérienne de l’infection ou un génotype particulier de la bactérie, pourraient être associés aux cas d'échec de traitement et d’infection persistante. Pour ce faire, une étude rétrospective de type cas-témoins composée de 204 patients ayant eu deux épisodes de chlamydiose génitale ou plus entre 2002 et 2012 (506 spécimens cliniques analysés au total) a été mise sur pied. En se servant de Campylobacter jejuni comme organisme modèle, il a été possible de développer une nouvelle méthode de détection moléculaire des mutations ponctuelles basée sur la PCR en temps réel, que nous avons nommée TaqTm Probing. Cette méthode a par la suite été exploitée pour chercher des mutations pouvant conférer une résistance à l’azithromycine chez C. trachomatis. Toujours par PCR en temps réel, une méthode d’évaluation semi-quantitative de la charge bactérienne des spécimens cliniques a aussi été mise au point et les spécimens ont été caractérisés par le typage de la protéine majeur de la membrane externe. Aucun cas de résistance n'a été observé, ni d’ailleurs de lien entre la charge bactérienne et l’évolution de l'infection vers un état de persistance ou d'échec de traitement. Par contre, il s'est avéré qu'une infection par le génotype E était significativement associée aux cas d'échec de traitement et d'infection persistante et augmentait le risque de survenue. Il sera important d'identifier subséquemment les mécanismes moléculaires impliqués.

Contexte : L'infection génitale à Chlamydia trachomatis (C. trachomatis ) est un important problème de santé publique car elle peut entraîner de graves séquelles en matière de reproduction, y compris l'atteinte inflammatoire pelvienne, l'infertilité tubaire et la grossesse ectopique. On retrouve une absence de symptômes de l'infection à C. trachomatis chez 70% des femmes infectées ce qui apporte une morbidité élevée car, même si l'infection est facilement curable, elle doit d'abord être dépistée. Objectif : L'objectif principal de la recherche est d'établir le risque de développer un problème de fertilité féminine après une infection à C. trachomatis et sa récidive. Méthode : L'étude de cohorte rétrospective, qui a eu lieu entre les années 1996 et 2011, a permis l'observation de deux groupes de femmes, âgées entre 15 et 24 ans, selon leur exposition à une infection à C. trachomatis . Avec une médiane de 7 ans pour le temps de suivi, les analyses de régressions se sont portées principalement sur les issues de reproduction telles que la naissance et le diagnostic d'infertilité tubaire. L'échantillon est constitué de 5,057 femmes qui ont effectué 12,301 examens de C. trachomatis avec seulement 8,6% de tests positifs. Résultat : Les analyses semblent démontrer que le potentiel d'accoucher est significativement moindre chez les femmes qui ont été exposées à une infection à C. trachomatis , pour un rapport de cote brut de 0,82 (IC à 95% : 0,67-0,99) et un RC ajusté, pour l'âge et d'autres infections vaginales, de 0,84 (0,69-1,02). Lorsqu'on stratifie selon l'âge, le RC ajusté indique 0,71; IC 95% (0,53-0,94) pour le groupe des 20-24 ans alors qu'il est sans effet chez les 15-19 ans. En ce qui concerne l'infertilité, on constate un risque significatif 3 fois plus élevé de développer une infertilité tubaire, RC brut de 2,81 (1,04-7,56), après avoir obtenu au moins une infection à C. trachomatis . Lorsqu'on ajuste pour l'âge, la tendance indique un RC ajusté de 1,52 (0,41-2,75). Conclusion : Les résultats de cette étude suggèrent qu'une infection à C. trachomatis contribue à l'infertilité tubaire et diminue le taux de natalité chez une femme. L'impact de l'infection se manifeste principalement chez les femmes âgées entre 20 et 24 ans lorsque la durée de suivi est minimalement de 4 ans suite au premier test à C. trachomatis . La détection et le traitement de l'infection doit se faire, particulièrement chez les femmes asymptomatiques, avant le développement de séquelles. La fréquence du dépistage doit être suffisante pour permettre une détection précoce.