The Role of MicroRNA-155 in Chlamydia muridarum Infected lungs.
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ABSTRACT:
SUBMITTER: Keck J
PROVIDER: S-EPMC7434643 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chlamydia trachomatis infections are the most prevalent sexually transmitted infections with potentially debilitating sequelae, such as infertility. Mouse models are generally used for vaccine development, to study the immune response and histopathology associated with Chlamydia infection. An important question regarding murine models is the in vivo identification of murine host genes responsible for the elimination of the murine and human Chlamydia strains. RNA sequencing of the Chlamydia muridarum infected BALB/c lung transcriptome revealed that several genes with direct antichlamydial functions were induced at the tissue level, including the already described and novel members of the murine interferon-inducible GTPase family, the CXCL chemokines CXCL9, CXCL11, immunoresponsive gene 1, nitric oxide synthase-2 (iNOS), and lipocalin-2. Indoleamine 2,3-dioxygenase 1-2 (IDO1-2) previously described potent antichlamydial host enzymes were also highly expressed in the infected murine lungs. This finding was novel, since IDO was considered as a unique human antichlamydial defense gene. Besides a lower level of epithelial cell positivity, immunohistochemistry showed that IDO1-2 proteins were expressed prominently in macrophages. Detection of the tryptophan degradation product kynurenine and the impact of IDO inhibition on Chlamydia muridarum growth proved that the IDO1-2 proteins were functionally active. IDO1-2 activity also increased in Chlamydia muridarum infected C57BL/6 lung tissues, indicating that this phenomenon is not mouse strain specific. Our study shows that the murine antichlamydial response includes a variety of highly up-regulated defense genes in vivo. Among these genes the antichlamydial effectors IDO1-2 were identified. The potential impact of murine IDO1-2 expression on Chlamydia propagation needs further investigation.
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Project description:Anti-chlamydial immunity involves efficient presentation of antigens (Ag) to effector cells resulting in Ag-specific immune responses. There is limited information on inherent underlying mechanisms regulating these events. Previous studies from our laboratory have established that select microRNAs (miRs) function as molecular regulators of immunity in Chlamydia muridarum (Cm) genital infection. In this report, we investigated immune cell type-specific miRs, i.e. miR-155 and -182, and the role in Ag-specific immunity. We observed significant up-regulation of miR-155 in C57BL/6 bone marrow derived dendritic cells (BMDC), and miR-182 in splenic Ag-specific CD4+ T-cells. Using mimics and inhibitors, we determined that miR-155 contributed to BMDC activation following Cm infection. Co-cultures of miR-155 over-expressed in BMDC and miR-182 over-expressed in Ag-specific CD4+ T-cells, or miR-155-/- BMDC with miR-182 inhibitor treated Ag-specific CD4+ T-cells, resulted in IFN-? production comparable to Ag-specific CD4+ T-cells isolated from Cm infected mice. Additionally, miR-182 was significantly up-regulated in intranasally vaccinated mice protected against Cm infection. In vivo depletion of miR-182 resulted in reduction in Ag-specific IFN-? and genital pathology in Cm infected mice. To the best of our knowledge, this is the first study to report an interaction of miR-155 (in Cm infected DC) and miR-182 (in CD4+ T-cell) resulting in Ag specific immune responses against genital Cm.
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Project description:Plasmid-free Chlamydia trachomatis and Chlamydia muridarum fail to induce severe pathology. To evaluate whether the attenuated pathogenicity is due to insufficient infection or inability of the plasmidless chlamydial organisms to trigger pathological responses, we compared plasmid-competent and plasmid-free C. muridarum infections in 5 different strains of mice. All 5 strains developed hydrosalpinx following intravaginal inoculation with plasmid-competent, but not inoculation with plasmid-free, C. muridarum. The lack of hydrosalpinx induction by plasmid-free C. muridarum correlated with significantly reduced live organism recovery from the lower genital tract and shortened infection in the upper genital tract. The plasmid-free C. muridarum organisms failed to induce hydrosalpinx even when the organisms were directly inoculated into the oviduct via an intrabursal injection, which was accompanied by significantly reduced survival of the plasmidless organisms in the genital tracts. Furthermore, plasmid-competent C. muridarum organisms after UV inactivation were no longer able to induce hydrosalpinx even when directly delivered into the oviduct at a high dose. Together, these observations suggest that decreased survival of and shortened infection with plasmid-free C. muridarum may contribute significantly to its attenuated pathogenicity. We conclude that adequate live chlamydial infection in the oviduct may be necessary to induce hydrosalpinx.
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Project description:To identify immunodominant antigens and MHC-restricted antibody responses, seven different strains of mice were intravaginally infected with Chlamydia muridarum and compared for antibody responses to 257 C. muridarum proteins. The 7 strains of mice recognized a total of 109 proteins as antigens, of which, 5 antigens (TC0660, TC0727, TC0828, TC0726 & TC0268) were each recognized by 60% or more mice from each mouse strain and thus designated as immunodominant antigens. Furthermore, antibody responses to 19 other antigens displayed strong associations with mouse H-2 haplotypes, including 6 antigens (TC0480, TC0912, TC0229, TCA04, TC0289 & TC0892) whose antibody responses were linked to H-2(b), 8 (TC0035, TC0387, TC0052, TC0781, TC0373, TC0117, TC0066 & TC0396) to H-2(d) and 5 (TC0512, TC0177, TC0589, TC0794 & TC0596) to H-2(k) haplotypes respectively. Interestingly, H-2(b) was negatively associated with antibody responses to most of the antigens that were positively linked to H-2(d) or H-2(k) haplotypes. These results by mapping Chlamydia trachomatis antigens commonly recognized by mice with different strain background and H-2 genes and revealing antigen association with H-2 haplotypes have provided important information for developing chlamydial subunit vaccines and understanding chlamydial pathogenesis.
| S-EPMC3377844 | biostudies-literature
Project description:The first step in attachment of Chlamydia to host cells is thought to involve reversible binding to host heparan sulfate proteoglycans (HSPGs), polymers of variably sulfated repeating disaccharide units coupled to diverse protein backbones. However, the key determinants of HSPG structure that are involved in Chlamydia binding are incompletely defined. A previous genome-wide Drosophila RNAi screen suggested that the level of HSPG 6-O sulfation rather than the identity of the proteoglycan backbone maybe a critical determinant for binding. Here, we tested in mammalian cells whether SULF1 or SULF2, human endosulfatases, which remove 6-O sulfates from HSPGs, modulate Chlamydia infection. Ectopic expression of SULF1 or SULF2 in HeLa cells, which decreases cell surface HSPG sulfation, diminished C.?muridarum binding and decreased vacuole formation. ShRNA depletion of endogenous SULF2 in a cell line that primarily expresses SULF2 augmented binding and increased vacuole formation. C.?muridarum infection of diverse cell lines resulted indownregulation of SULF2 mRNA. In a murine model of acute pneumonia, mice genetically deficient in both endosulfatases or in SULF2 alone demonstrated increased susceptibility to C.?muridarum lung infection. Collectively, these studies demonstrate that the level of HSPG 6-O sulfation is a critical determinant of C.?muridarum infection in vivo and that 6-O endosulfatases are previously unappreciated modulators of microbial pathogenesis.
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Project description:Pathogenically diverse Chlamydia spp. can have surprisingly similar genomes. Chlamydia trachomatis isolates that cause trachoma, sexually transmitted genital tract infections (chlamydia), and invasive lymphogranuloma venereum (LGV) and the murine strain Chlamydia muridarum share 99% of their gene content. A region of high genomic diversity between Chlamydia spp. termed the plasticity zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and gamma interferon (IFN-γ) resistance of C. muridarum compared to C. trachomatis in the murine genital tract. To test this hypothesis, we isolated and characterized a series of C. muridarum PZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins, guaBA-add, and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than the wild type, suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-γ sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest that C. muridarum PZ genes are transcribed--and some may produce functional proteins--but are dispensable for infection of the murine genital tract.
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Project description:Urogenital infection with Chlamydia trachomatis in some women can lead to upper genital tract pathologies, such as hydrosalpinx, potentially affecting fertility. In the current study, 27 of 40 mice intravaginally infected with Chlamydia muridarum developed visible hydrosalpinges in the oviduct while the remaining 13 did not, although all infected mice displayed similar infection time courses. Antisera from the 40 mice recognized 130 out of 257 C. muridarum proteins as antigens and 17 as immunodominant antigens. Importantly, the 27 mice with hydrosalpinges preferentially recognized two C. muridarum proteins (TC0582 and TC0912, designated pathology-associated antigens) while the 13 mice with no hydrosalpinx preferentially recognized 10 proteins (TC0047, TC0117, TC0190, TC0197, TC0257, TC0279, TC0326, TC0630, TC0689, and TC0816, designated nonpathology antigens). The preferential recognition was validated by absorption and independently confirmed in Western blots. The C. trachomatis homolog of TC0912 is encoded by a highly polymorphic gene that is associated with ocular pathogenesis. A fragment of TC0912 was found to improve the differentiation of hydrosalpinx from nonhydrosalpinx mice. TC0582 is a highly conserved ATP synthase, and it may contribute to chlamydial pathogenesis via mechanisms similar to those hypothesized for the highly conserved HSP60. Thus, we have identified chlamydial antigens and epitopes that are associated with either susceptibility or resistance to upper genital tract pathology, which will help us to further understand chlamydial pathogenesis and to develop anti-Chlamydia subunit vaccines.
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Project description:In women, Chlamydia trachomatis can ascend from the cervix to the fallopian tubes, where an overly aggressive host inflammatory response can cause scarring that leads to chronic pelvic pain, infertility, or ectopic pregnancy. Although screening and treatment programs for women have resulted in decreased rates of sequelae, morbidities associated with oviduct scarring continue to occur. Since corticosteroids have anti-inflammatory and antifibrotic effects, we tested the ability of dexamethasone to inhibit inflammation and prevent oviduct scarring in mice genitally infected with Chlamydia muridarum. The administration of 1 or 2.5 mg/kg of body weight of dexamethasone on days 7 to 21 of infection resulted in reduced accumulation of inflammatory cells in the oviducts compared to that in controls. However, a concomitant increase in bacterial burden was observed, and chronic oviduct disease was not reduced. Adjunctive administration of a prolonged (21-day) or short (3-day) course of dexamethasone in combination with the antibiotic doxycycline also failed to reduce chronic oviduct pathology compared to antibiotic treatment alone. Steroids administered alone or adjunctively with antibiotics failed to prevent oviduct damage in this murine model of C. trachomatis infection.
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