Az atherosclerosis és Chlamydia pneumoniae fertőzések összefüggésének genetikai háttere = The genetic background of the interactions between atherosclerosis and Chlamydia pneumoniae infections

Atherosclerotikus plakkokban gyakran a Chlamydophila pneumoniae (C. pneumoniae) DNS és human cytomegalovirus (HCMV) DNS közös jelenléte mutatható ki. A kettősen fertőzött monocytákban az atherosclerosisban szerepet játszó gének expressziója jön létre. A HCMV-vel (Oslo törzs) fertőzött dendritikus sejtekben (DC) a virus nem szaporodik, de a HCMV-vel fertőzött fibroblast sejtek által termelt faktorok a DC érését indítják el. A DC fertőzése C. pneumoniae-val elindítja a DC érését, de a fertőző baktériumok szaporodasát nem. Bizonyos chlamydiális transzkriptok kifejezőséde megtörténik, de a baktérium osztódásásban szerepet jatszó ftsK gén mRNA expressziója nem. Akut nem-cardioembóliás eredetű stroke betegek és kontroll egyének vérének vizsgálata szerint a CD14 és IL-8 promoter polimorfizmusok nem jatszanak szerepet a stroke kialakulásában. A stroke betegekben szignifikánsan magasabb a HCMV-IgG és HSV-1 IgA ellenanyag szint. Percutan transluminalis angioplasztikai beavatkozás után a C. pneumoniae DNS és HCMV DNS kimutathatósága fokozott, a hisztamin, CRP, és IL-6 szintek emelkedettek. Egér modellen az egyszeri vagy ismételt C. pneumoniae fertőzés bakteriális perzisztenciát eredményez. | Chlamydophila pneumoniae (C. pneumoniae) is often present in combination with human cytomegalovirus (HCMV) in atherosclerotic carotid lesions. The doubly-infected monocytes are potent expressors of proatherosclerotic genes. The HCMV (strain Oslo) does not replicate in infected dendritic cells (DC), however HCMV conditioning medium harvested from human fibroblast cells induce the expression of maturation markers on the DC. Full replication of C. pneumoniae in DC is not observed, but C. pneumoniae infection induce the maturation and functional activation of DC. Some chlamydial genes are expressed, but the expression of the division-related ftsK gen is limited. By analyzing blood samples of patients with acute noncardioembolic ischemic stroke and control individuals, the IL-8 or CD14 promoter polymorphisms are not related with the development of the disease. Serum levels of HCMV-IgG and HSV-1 IgA are higher in the patients than in the controls. Reactivation of C. pneumoniae and HCMV and increased levels of histamine, CRP and IL-6 followoing percutan transluminal angioplasty are observed. A single or repeated inoculation of mice with C. pneumoniae result in bacterial persistence in a few mice

Independent and joint effects of antibodies to human heat-shock protein 60 and Chlamydia pneumoniae infection in the development of coronary atherosclerosis

Background—Studies have suggested that the prevalence of antibodies against heat-shock proteins (HSPs), Chlamydia pneumoniae (Cpn), and cytomegalovirus (CMV) is associated with coronary artery disease (CAD), but the independent or joint effects of human (h) HSP60 antibodies and these pathogens in patients have not been fully elucidated. Methods and Results—A total of 405 subjects (276 patients with CAD and 129 control individuals) were tested for serum antibodies to hHSP60, Cpn, and CMV immediate-early-1 (IE1) antigens. Patients were also assessed for serum cholesterol, triglyceride levels, and smoking habit. Significantly elevated levels of antibodies to hHSP60 and Cpn but not to CMV-IE1 antigens were documented in CAD patients. Multiple logistic regression analysis and subanalyses of selected subjects showed that these associations were independent of age, sex, smoking, and serum lipid levels. Antibodies to hHSP60 and Cpn did not correlate quantitatively; however, the relative risk of disease development was substantially increased in subjects with high antibody levels to both hHSP60 and Cpn, reaching an odds ratio of 82.0 (95% CI 10.6 to 625.0). Conclusions—High levels of antibodies to hHSP60 and Cpn are independent risk factors for coronary atherosclerosis, but their simultaneous presence substantially increases the risk for disease development

Immunization of Chlamydia pneumoniae (Cpn)-infected Apob(tm2Sgy)Ldlr(tm1Her)/J mice with a combined peptide of Cpn significantly reduces atherosclerotic lesion development

OBJECTIVE: To investigate the antigenic effect of a peptide containing two epitopes of Chlamydia pneumoniae (Cpn) on atherosclerotic lesion formation in mice infected with Cpn. MATERIALS AND METHODS: Six-week-old Apob(tm2Sgy)Ldlr(tm1Her)/J mice were immunized using a repetitive immunization multiple-sites strategy with KLH-conjugated peptides derived from the major outer membrane protein and the putative outer membrane protein 5 of Cpn. Mice were fed a high-fat diet and infected with Cpn twice during the 10-week diet period. Lesions were evaluated histologically; local and systemic immune responses were analyzed by immunohistochemistry of aorta samples and cytokine measurements in plasma samples and splenocyte supernatants. RESULTS: Mice immunized with the combined Cpn peptide showed a greater reduction in lesion size compared to mice immunized with either epitope alone [54.7% vs 39.8% or 41.72%] and was also associated with a significant decrease in lesion area in descending aortas compared with those in controls (88.9% for combined Cpn peptide, 81.9% for MOMP peptide and 75.7% for Omp5, respectively). This effect was associated with a shift in the cellular composition of plaques towards decreased inflammatory cell and increased regulatory T-cell content. Additionally, the effect was also connected with decreased secretion of proinflammatory cytokines and increased production of anti-inflammatory cytokines demonstrated in plasma and in supernatant on stimulated spleen cells. CONCLUSIONS: Atherosclerotic lesion formation may be promoted by Cpn infection in the presence of a high-fat diet, and reduced by immunization with the combined Cpn peptide. The combined peptide has more potential than either epitope alone in reducing atherosclerotic lesion development through Treg expansion

Association of Chlamydia pneumoniae with coronary artery disease and its progression is dependent on the modifying effect of mannose-binding lectin

Background— The possible association between coronary artery disease (CAD) and Chlamydia pneumoniae (C pneumoniae) infection is controversial. On the basis of the recent suggestion that mannose-binding lectin (MBL) variant alleles are related to an increased risk of severe atherosclerosis, and on the in vitro interaction of MBL with C pneumoniae, we asked whether MBL might contribute to CAD in conjunction with C pneumoniae. Methods and Results— Antibodies to C pneumoniae were measured by immunofluorescence and MBL alleles were determined by polymerase chain reaction technique in samples from 210 patients with CAD and 257 healthy subjects from Hungary collected between 1995 and 1996. A higher percentage of patients with CAD were anti-C pneumoniae positive as compared with the control group (P=0.058). However, at logistic regression analysis adjusted to age, sex, and serum lipid levels, this difference was confined only to subjects carrying MBL variant alleles (P=0.035, odds ratio 2.63, [95% CI: 1.07 to 6.45]). In contrast, no significant difference was seen in those homozygous for the normal MBL allele (P=0.412). During a 65±5.8-month follow-up period, major outcomes (new myocardial infarction, and/or bypass operation or cardiovascular death) occurred in 11 C pneumoniae positive and 3 C pneumoniae negative patients. In the C pneumoniae positive group, the odds ratio of development of outcomes was 3.27 (95% CI: 1.10 to 9.71, P=0.033) in the carriers of the MBL variant alleles compared with the homozygous carriers of the normal MBL allele. Conclusions— These results indicate that infection with C pneumoniae leads mainly to the development and progression of severe CAD in patients with variation in the MBL gene

N-acetyl-cysteine increases the replication of Chlamydia pneumoniae and prolongs the clearance of the pathogen from mice

PURPOSE: Within the community, 10 % of acquired pneumonia is caused by Chlamydia pneumoniae. N-acetyl-cysteine (NAC) is one of the most commonly used mucolytics in respiratory diseases, but its effect on C. pneumoniae infection has not yet been investigated. In this study, our aim was to investigate whether NAC influences the replication of C. pneumoniae. After determining that NAC does have an effect on C. pneumoniae replication, the effect of an alternative drug called Ambroxol (Ax) was investigated. METHODOLOGY: The in vitro effect of NAC and Ax was studied on C. pneumoniae-infected A549 and McCoy cells. Furthermore, the influence of NAC and Ax was examined in mice infected intranasally with C. pneumoniae. RESULTS: NAC treatment resulted in approximately sixfold more efficient C. pneumoniae growth in tissue culture compared to the untreated control cells, and this effect was shown to be based on the increased binding of the bacterium to the host cells. The C. pneumoniae-infected mice to which NAC was given had prolonged and more severe infections than the control mice. Ax decreased C. pneumoniae replication in vitro, which was partially associated with the increased expression of indolamine 2,3-dioxygenase. In animals, using the adapted usual human dose, Ax did not alter the number of recoverable C. pneumoniae. CONCLUSION: Based on our results, it might be recommended that a mucolytic agent other than NAC, such as Ax, be used in respiratory diseases suspected to be caused by C. pneumoniae

Liposomal Encapsulation Increases the Efficacy of Azithromycin against Chlamydia trachomatis

Chlamydia trachomatis (C. trachomatis) is an obligate intracellular bacterium linked to ocular and urogenital infections with potentially serious sequelae, including blindness and infertility. First-line antibiotics, such as azithromycin (AZT) and doxycycline, are effective, but treatment failures have also been reported. Encapsulation of antibiotics in liposomes is considered an effective approach for improving their local effects, bioavailability, biocompatibility and antimicrobial activity. To test whether liposomes could enhance the antichlamydial action of AZT, we encapsulated AZT in different surface-charged elastic liposomes (neutral, cationic and anionic elastic liposomes) and assessed their antibacterial potential against the C. trachomatis serovar D laboratory strain as well as the clinical isolate C. trachomatis serovar F. A direct quantitative polymerase chain reaction (qPCR) method was used to measure chlamydial genome content 48 h post infection and to determine the recoverable chlamydial growth. All the liposomes efficiently delivered AZT to HeLa 229 cells infected with the laboratory Chlamydia strain, exhibiting the minimal inhibitory concentrations (MIC) and the minimal bactericidal concentrations (MBC) of AZT even 4-8-fold lower than those achieved with the free AZT. The tested AZT-liposomes were also effective against the clinical Chlamydia strain by decreasing MIC values by 2-fold relative to the free AZT. Interestingly, the neutral AZT-liposomes had no effect on the MBC against the clinical strain, while cationic and anionic AZT-liposomes decreased the MBC 2-fold, hence proving the potential of the surface-charged elastic liposomes to improve the effectiveness of AZT against C. trachomatis

Vaginal Gel Component Hydroxyethyl Cellulose Significantly Enhances the Infectivity of Chlamydia trachomatis Serovars D and E

The transmission of the urogenital serovars of Chlamydia trachomatis can be significantly influenced by vaginal gels. Hydroxyethyl cellulose is a commonly used gelling agent that can be found in vaginal gels. Hydroxyethyl cellulose showed a concentration-dependent growth-enhancing effect on C. trachomatis serovars D and E, with a 26.1-fold maximal increase in vitro and a 2.57-fold increase in vivo