Imiquimod Does not Affect Shedding of Viable Chlamydiae in a Murine Model of Chlamydia trachomatis Genital Tract Infection

Objective: We postulated that either oral or vaginal administration of the immune response modifier imiquimod would decrease vaginal shedding of Chlamydia trachomatis, mouse pneumonitis strain (MoPn), in a murine model. Methods: Female BALB/c mice were infected intravaginally withC. trachomatis (MoPn) and were administered imiquimod either orally (30 mg/kg) or vaginally (10 μl of 5%imiquimod cream) prior to infection and every second day after infection for a total of four doses. The course of infection was monitored by collecting cervical–vaginal swabs and isolation in HeLa 229 cell culture. To determine whether the drug affected T helper type 1 or T helper type 2 immune response polarization, immunoglobulinG(IgG) subclass antibody responses were assessed at day 56 after infection. Results: There was no significant difference in the course of infection when imiquimod-treated mice were compared with sham-treated controls, regardless of whether the drug was administered orally or vaginally. IgG subclass antibody responses, and by extension, T helper type 1 to T helper type 2 immune response polarization, were also unaffected. Conclusions: Imiquimod has no efficacy in controllingC. trachomatis (MoPn) infection in the murine model

Identification of Novel Single Nucleotide Polymorphisms in Inflammatory Genes as Risk Factors Associated with Trachomatous Trichiasis

infection, the primary cause of trachoma. Despite control programs that include mass antibiotic treatment, reinfection and recurrence of trachoma are common after treatment cessation. Furthermore, a subset of infected individuals develop inflammation and are at greater risk for developing the severe sequela of trachoma known as trachomatous trichiasis (TT). While there are a number of environmental and behavioral risk factors for trachoma, genetic factors that influence inflammation and TT risk remain ill defined. = 0.001] with the combination of TNFA (-308A), LTA (252A), VCAM1 (-1594C), SCYA 11 (23T) minor allele, and the combination of TNFA (-308A), IL9 (113M), IL1B (5′UTR-T), and VCAM1 (-1594C). However, TT risk increased 13.5 times [odds ratio = 13.5 (95% confidence interval 3.3–22), p = 0.001] with the combination of TNFA (-308G), VDR (intron G), IL4R (50V), and ICAM1 (56M) minor allele.Evaluating genetic risk factors for trachoma will advance our understanding of disease pathogenesis, and should be considered in the context of designing global control programs

Interleukin-13 Promotes Susceptibility to Chlamydial Infection of the Respiratory and Genital Tracts

Chlamydiae are intracellular bacteria that commonly cause infections of the respiratory and genital tracts, which are major clinical problems. Infections are also linked to the aetiology of diseases such as asthma, emphysema and heart disease. The clinical management of infection is problematic and antibiotic resistance is emerging. Increased understanding of immune processes that are involved in both clearance and immunopathology of chlamydial infection is critical for the development of improved treatment strategies. Here, we show that IL-13 was produced in the lungs of mice rapidly after Chlamydia muridarum (Cmu) infection and promoted susceptibility to infection. Wild-type (WT) mice had increased disease severity, bacterial load and associated inflammation compared to IL-13 deficient (−/−) mice as early as 3 days post infection (p.i.). Intratracheal instillation of IL-13 enhanced bacterial load in IL-13−/− mice. There were no differences in early IFN-g and IL-10 expression between WT and IL-13−/− mice and depletion of CD4+ T cells did not affect infection in IL-13−/− mice. Collectively, these data demonstrate a lack of CD4+ T cell involvement and a novel role for IL-13 in innate responses to infection. We also showed that IL-13 deficiency increased macrophage uptake of Cmu in vitro and in vivo. Moreover, the depletion of IL-13 during infection of lung epithelial cells in vitro decreased the percentage of infected cells and reduced bacterial growth. Our results suggest that enhanced IL-13 responses in the airways, such as that found in asthmatics, may promote susceptibility to chlamydial lung infection. Importantly the role of IL-13 in regulating infection was not limited to the lung as we showed that IL-13 also promoted susceptibility to Cmu genital tract infection. Collectively our findings demonstrate that innate IL-13 release promotes infection that results in enhanced inflammation and have broad implications for the treatment of chlamydial infections and IL-13-associated diseases

An in vitro model for immune control of chlamydial growth in polarized epithelial cells.

A polarized epithelial culture system and chlamydia-specific T-cell lines and clones were employed to investigate the ability and mechanisms by which T cells control the growth of chlamydiae in epithelial cells. Monolayers of polarized mouse epithelial cells were infected with the Chlamydia trachomatis agent of mouse pneumonitis (MoPn) and then exposed to antigen-stimulated MoPn-specific T-cell lines and clones. The results revealed that in vivo-protective MoPn-specific T-cell lines and clone 2.14-0 were capable of inhibiting the growth of MoPn in polarized epithelial cells. In contrast, the nonprotective MoPn-specific T-cell clone 2.14-3, naive splenic T cells, and a control T-cell clone could not inhibit the growth of MoPn in epithelial cells. Transmission electron microscopic analysis of infected epithelial cells which were exposed to clone 2.14-0 confirmed the absence of an established infection, as deduced from the virtual absence of inclusions in the cells. Antigen-specific activation of clone 2.14-0 was required for the MoPn-inhibitory function, since the absence of antigenic stimulation or stimulation with a heterologous chlamydial agent did not result in MoPn growth inhibition. Activation of clone 2.14-0 resulted in acquisition of the capacity to inhibit growth of both homologous (MoPn) and heterologous chlamydial agents. Close interaction between epithelial cells and clone 2.14-0 was required for the MoPn-inhibitory action, because separation of the cell types by a filter with a pore size of 0.45, 3.0, or even 8.0 microns abrogated MoPn inhibition. Protective T cells may act at close range in the epithelium to control chlamydial growth, possibly involving short-range-acting cytokines. The ability of antigen-stimulated T-cell lines and clones to inhibit chlamydial growth in polarized epithelial cultures could be a useful method for identifying protective T-cell clones and antigenic peptide fragments containing protective epitopes