Persistent Chlamydial Infection Research Articles

Sex and Shedding of Human Immunodeficiency Virus

To the Editor?By distinguishing between women who ovulated during the menstrual cycle and those who did not ovulate, Greenblat et al. [1] found that sex, contrary to generally accepted opinion, influences circulating human immunodeficiency virus (HIV) type 1 RNA levels. In ovulating women, the virus load fell during the early follicular phase through the midluteal phase. Furthermore, cervicovaginal shedding of HIV among pregnant women was higher than it was among nonpregnant women with moreadvanced HIV disease [2]. Since the hormonal balances of pregnant and nonpregnant women differ, the effects of ovulation and of pregnancy on HIV RNA levels seem to point to a connection with reproductive hormones. However, the mechanisms of both phenomena are not wholly understood. It may, therefore, be of interest to investigate similar phenomena in animals. In sheep infected experimentally with Chlamydia psittaci, shedding of the microorganism occurs only during the periovicular phase of the estrous cycle [3]. Detectable levels of chlamydiae obtained by vaginal swabs collected during different stages of the ewe's estrous cycle were restricted to the day of ovulation until ~4 days later. Of note, a persistent chlamydial infection of the ewe's reproductive tract occurred after the experimental infection. The periovicular, increased shedding of C. psittaci in sheep and the influence of ovulation in women on the fluctuation in plasma HIV RNA level [1] seem to support the significance of changes related to reproductive ability. Another comparison relates to birds. In some of 19 orders of birds examined over 4 years in Israel, shedding of C. psittaci was

Cytotoxic-T-lymphocyte-mediated cytolysis of L cells persistently infected with Chlamydia spp.

Persistent chlamydial infections have been proposed as a means whereby chlamydiae evade immune resolution of infection. Such a mechanism would require evasion not only of the humoral immune responses but also of cell-mediated immune responses. We hypothesized that if such a mechanism is important, persistently infected cells should not be recognized by cytotoxic T cells. Persistent infections were simulated in vitro by treatment of Chlamydia trachomatis- or Chlamydia psittaci-infected cells with gamma interferon (IFN-gamma), penicillin, or tryptophan depletion. Cultures were examined for induction of a chlamydial stress response (measured by transcription of groesl RNA) and for the effects on viability, infectivity, morphology, and immune recognition. Although both IFN-gamma and penicillin induced aberrant chlamydial morphology and growth, we did not find evidence that these treatments elicited a classical stress response. In addition, T-cell-mediated lysis of Chlamydia-infected target cells treated with IFN-gamma or penicillin or grown in tryptophan-deficient media was examined. The immune cell-mediated lysis of these treated infected cells demonstrated that despite the effects of these compounds on chlamydial growth and development, the infected cells continued to be efficiently recognized and killed by cytotoxic T cells. Thus, it seems unlikely that these in vitro models of persistence represent functional mechanisms to evade immune clearance.

Persistent chlamydial infections: An in vivo reality or a cell culture artifact?

Persistent chlamydial infections: An in vivo reality or a cell culture artifact?

Reactivation of persistent Chlamydia trachomatis infection in cell culture.

Gamma interferon induces persistent chlamydial infections in cell culture. These infections are characterized by altered morphologic and biochemical features of the pathogen. These persistent forms are abnormally large and noninfectious and undergo unusual structural and functional changes, including production of a paucity of outer envelope constituents and normal levels of the chlamydial hsp60, an immunopathological antigen. The current investigation evaluates the events that occur during reactivation of infectious Chlamydia trachomatis from persistently infected cell cultures. Transfer of persistent chlamydial organisms to gamma interferon-free medium resulted in recovery of infectivity accompanied by an increase in levels of structural membrane proteins and reorganization of aberrant organisms to morphologically typical elementary bodies. In addition, reactivation of infectious organisms from persistent chlamydiae that were maintained in culture for several weeks was demonstrated. These studies show that persistent C. trachomatis maintains viability for extended periods, illustrate the reversibility of immunologically mediated persistent infections, and characterize reactivation at the ultrastructural and biochemical levels.

Tryptophan depletion as a mechanism of gamma interferon-mediated chlamydial persistence

Previous studies have shown that the immune-regulated cytokine gamma interferon (IFN-gamma) activates host cells to restrict intracellular growth of the bacterial pathogen Chlamydia trachomatis by induction of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Recently, subinhibitory levels of IFN-gamma were used to generate an in vitro persistent chlamydial infection characterized by large aberrant, noninfectious reticulate bodies from which infectious progeny could be recovered following the removal of IFN-gamma. Studies were done to determine if the mechanism functioning to induce chlamydiae to enter a persistent state in the presence of low levels of IFN-gamma was similar to that reported to inhibit chlamydial growth. Host cells treated with levels of IFN-gamma required to induce persistence were assessed for IDO activity by high-performance liquid chromatography analysis of tryptophan and its catabolic products. Substantial tryptophan catabolism was detected in acid-soluble cellular pools, indicating that the intracellular availability of this essential amino acid was limited under these conditions. In addition, a mutant cell line responsive to IFN-gamma but deficient in IDO activity was shown to support C. trachomatis growth, but aberrant organisms were not induced in response to IFN-gamma treatment. Analyses of infected cells cultured in medium with incremental levels of exogenous tryptophan indicated that persistent growth was induced by reducing the amount of this essential amino acid. These studies confirmed that nutrient deprivation by IDO-mediated tryptophan catabolism was the mechanism by which IFN-gamma mediates persistent growth of C. trachomatis.

Clinically silent infections in patients with oligoarthritis: results of a prospective study.

Oligoarticular synovitis of undetermined origin can closely resemble an incomplete form of reactive arthritis/Reiter's syndrome. Eighty three patients with oligoarthritis of undetermined origin were studied prospectively to identify asymptomatic infections potentially triggering the inflammatory response in the synovial fluid. At the time of initial evaluation, 57 (69%) of the patients with oligoarthritis and 4/20 (20%) of the control subjects were carriers of clinically silent infections. Evidence for persistent or prior chlamydial infections was frequently and exclusively found in the study group (30/83 (36%) patients v no controls), whereas undetected urogenital infections with mycoplasma were present in nine (11%) patients and four (20%) controls. Eleven (13%) of the patients carried cellular and humoral responses to Borrelia burgdorferi. The HLA-B27 haplotype represented a major risk factor for the development of oligoarthritis but not for development of sacroiliitis. Re-evaluation after one year showed that the course and outcome of the oligoarticular disease did not correlate with a specific infectious organism and were not affected by antibiotic treatment sufficient to treat the carrier state.

Implications for persistent chlamydial infections of phagocyte-microorganism interplay

In vitro models of Chlamydia trachomatis inhibition by cytokines, human-monocyte derived macrophages (HMDM) and human polymorphonuclear leukocytes (HPMN) are discussed in an attempt to delineate the molecular basis of parasite-host cell interplay in persistent and chronic chlamydial infection. Interferon gamma (IFN) has been found to reversibly inhibit chlamydial growth at an early stage in the replicative cycle, while tumor necrosis factor (TNF) has a more profound effect on chlamydial growth resulting in production of aberrant reticulate bodies and enhancement of production of prostaglandin E2 (PGE2). Chlamydia trachomatis (serovar L2) replicate in HMDM while serovar K has been found to be restricted in these cells. Chlamydiae are killed by HPMN but the cell walls persist undegraded, inducing production of oxygen radicals which can be demonstrated to induce DNA strand scissions in HeLa target cells. Evidence is accumulating that chlamydia specific serum IgA antibodies may serve as a noninvasive serological marker for diagnosis of a number of acute and persistent Chlamydia trachomatis infections.

Neonatal Chlamydial Conjunctivitis

Chlamydia trachomatis (Ct) was isolated from eyes of 33 out of 160 infants with neonatal conjunctivitis. In nineteen (58%) of the infants with chlamydial conjunctivitis Ct could also be isolated from the nasopharynx. All infants were treated with oral erythromycin ethylsuccinate 25 mg/kg every 12 hours for 14 days combined with lid hygiene. All were clinically cured, and none had a relapse of clinical Ct conjunctivitis during an observation period of one year. However, one infant had persistent asymptomatic chlamydial eye infection, two displayed a persistent infection of the nasopharynx, and one infant's vagina was infected despite therapy. Serum IgG antibodies to Ct were significantly more often detected in clinical cases (90%) than in controls (33%) (p less than 0.01). Infants with conjunctivitis developed detectable IgM antibodies to Ct in 43% as compared to 7% in controls (p less than 0.01).

Failure of β-Lactam Antibiotics to Eradicate Chlamydia trachomatis in the Endometrium Despite Apparent Clinical Cure of Acute Salpingitis

Chlamydia trachomatis was isolated from 17 (24%) of 71 patients with acute salpingitis (AS) hospitalized for parenteral treatment. For patients with AS, antimicrobial therapy was started immediately on admission and before the availability of culture results. Notable clinical response was seen in 16 of 17 chlamydial-positive cases. Despite apparent clinical cure, posttreatment cultures from the endometrial cavity yielded C trachomatis from 12 of 13 patients treated solely with second- or third-generation cephalosporins as single-agent therapy. The finding of persistent chlamydial infection of the endometrium suggests that some patients treated for AS, despite apparent clinical response, maintain chlamydial infection of the endometrium that might cause relapse or chronic fallopian tube infection with tubal obstruction and infertility, or perhaps reflect a similar tubal persistence of Chlamydia. Treatment of AS should routinely include coverage for C trachomatis, as clinical response and findings may not reflect its presence or persistence.