Pseudomonas aeruginosa colonizes and infects human tissues, although the mechanisms by which the organism evades the normal, predominantly neutrophilic, host defenses are unclear. Phenazine products of P. aeruginosa can induce death in Caenorhabditis elegans. We hypothesized that phenazines induce death of human neutrophils, and thus impair neutrophil-mediated bacterial killing. We investigated the effects of two phenazines, pyocyanin and 1-hydroxyphenazine, upon apoptosis of neutrophils in vitro. Pyocyanin induced a concentration- and time-dependent acceleration of neutrophil apoptosis, with 50 μM pyocyanin causing a 10-fold induction of apoptosis at 5 h (p < 0.001), a concentration that has been documented in sputum from patients colonized with P. aeruginosa. 1-hydroxyphenazine was without effect. In contrast to its rapid induction of neutrophil apoptosis, pyocyanin did not induce significant apoptosis of monocyte-derived macrophages or airway epithelial cells at time points up to 24 h. Comparison of wild-type and phenazine-deleted strains of P. aeruginosa showed a highly significant reduction in neutrophil killing by the phenazine-deleted strain. In clinical isolates of P. aeruginosa pyocyanin production was associated with a proapoptotic effect upon neutrophils in culture. Pyocyanin-induced neutrophil apoptosis was not delayed either by treatment with LPS, a powerfully antiapoptotic bacterial product, or in neutrophils from cystic fibrosis patients. Pyocyanin-induced apoptosis was associated with rapid and sustained generation of reactive oxygen intermediates and subsequent reduction of intracellular cAMP. Treatment of neutrophils with either antioxidants or synthetic cAMP analogues significantly abrogated pyocyanin-induced apoptosis. We conclude that pyocyanin-induced neutrophil apoptosis may be a clinically important mechanism of persistence of P. aeruginosa in human tissue.
In general it is believed that apoptosis does not occur in C. trachomatis-infected host cells. However, using three different methods, our findings clearly indicate that co-incubation of sperm with C. trachomatis LPS results in cellular death which is in part due to apoptosis and is caspase-mediated. These findings provide an explanation as to how C. trachomatis can mediate premature death in human sperm.
The success of Streptococcus pneumoniae (the pneumococcus) as a pulmonary pathogen is related to its restriction of innate immune responses by respiratory epithelial cells. The mechanisms used to overcome this restriction are incompletely elucidated. Pulmonary chemokine expression involves complex cellular and molecular networks, involving the pulmonary epithelium, but the specific cellular interactions and the cytokines that control them are incompletely defined. We show that serotype 2 or 4 pneumococci induce only modest levels of CXCL8 expression from epithelial cell lines, even in the absence of a polysaccharide capsule. In contrast, coculture of A549 cells with the macrophage-like THP-1 cell line, differentiated with vitamin D, or monocyte-derived macrophages enhanced CXCL8 release. Supernatants from the THP-1 cell line prime A549 cells to release CXCL8 at levels similar to cocultures. Interleukin-1Ra (IL-1Ra) inhibits CXCL8 release from cocultures and reduces the activity of macrophage-conditioned media, but inhibition of tumor necrosis factor alpha (TNF-␣) had only a minimal effect on CXCL8 release. Release of IL-1 but not TNF-␣ was upregulated in cocultures. IL-1 type 1 receptor knockout C57BL/6 and BALB/c mice confirmed the importance of IL-1 signaling in CXC chemokine expression and neutrophil recruitment in vivo. In fulminant disease, increased IL-1 signaling resulted in increased neutrophils in the airway and more invasive disease. These results demonstrate that IL-1 is an important component of the cellular network involving macrophages and epithelial cells, which facilitates CXC chemokine expression and aids neutrophil recruitment during pneumococcal pneumonia. They also highlight a potential clinical role for anti-IL-1 treatment to limit excessive neutrophilic inflammation in the lung.
Chlamydia trachomatis infection can lead to pelvic inflammatory disease, ectopic pregnancy (EP), infertility, and chronic pelvic pain in women. Activins and inducible nitric oxide synthase (iNOS) are produced by the human fallopian tube, and we speculate that tubal activins and iNOS may be involved in the immune response to C. trachomatis in humans and their pathological alteration may result in tubal pathology and the development of EP. Blood and fallopian tubes were collected from 14 women with EP. Sera were analyzed by enzyme-linked immunosorbent assay to detect antibodies against chlamydial heat shock protein 60 (chsp60) and the major outer membrane protein of C. trachomatis. Confirmation of C. trachomatis serology was made using the microimmunofluorescence test. The patients were classified into three groups according to their serological results, and immunohistochemistry and quantitative reverse transcription-PCR were performed to investigate the expression of candidate molecules by tubal epithelial cells among the three groups. This is the first study to show an increase in the expression of activin A subunit, type II receptors, follistatin, and iNOS within the human fallopian tube of EP patients who were serologically positive for C. trachomatis. A similar expression profile was observed in the fallopian tubes with detectable antibodies only against chsp60. These results were shown at the mRNA and protein levels. We suggest that tubal activin A, its type II receptors, follistatin, and NO could be involved in the microbial-mediated immune response within the fallopian tube, and their pathological expression may lead to tubal damage and the development of EP.
SUMMARY Fourteen of 194 (7-2Vo) consecutive unselected men had positive culture results from genital swabs for Gardnerella vaginalis. A higher yield of isolates was obtained from preputial (93%) than from urethral swabs (647o). Of the 14 men, two had no detectable genital abnormality, eight non-gonococcal urethritis, and nine balanoposthitis. The urethral isolation rates for G vaginalis in men with and without non-gonococcal urethritis were not significantly different, but preputial isolation rates were significantly higher (P<0-001) in men with balanoposthitis than in those without. The prevalence rate for G vaginalis in men with non-candidal balanoposthitis was 31%qo.In a second study, concomitant Bacteroides species were isolated in preputial swabs from nine of 12 (750%o) men with G vaginalis-associated balanoposthitis and may play a role in its pathogenesis.
An open, randomized, culture-controlled clinical study was designed to compare the efficacy of a single 2 g dose of metronidazole (Elyzol) with standard 7-day therapy in the treatment of bacterial vaginosis (BV). Forty-one of 47 (87%) patients given the single dose and 30 of 33 (91%) given the 7-day treatment were found to be cured seven days after treatment. At final assessment, 24 of 34 (71%) patients given the single dose and 22 of 28 (79%) given the 7-day treatment remained cured. The two regimes were equally efficaceous in eradicating Gardnerella vaginalis, Bacteroides spp. and Mobiluncus spp. (anaerobic curved rods) from vaginal specimens from patients with BV. The in-vitro activity of metronidazole and its hydroxy metabolite was determined for 11 strains of Gard. vaginalis, 17 strains of Bacteroides spp. and 14 strains of Mobiluncus spp. which had been isolated from patients prior to treatment. The MIC of metronidazole against Gard. vaginalis varied between 2 and greater than or equal to 128 mg/l (median MIC 32 mg/l), but the hydroxy metabolite showed a markedly increased activity against eight of the strains tested (median MIC 4 mg/l). The MIC of metronidazole against the Mobiluncus spp. varied between 0.5 and greater than or equal to 128 mg/l (median MIC 16 mg/l) and the hydroxy metabolite showed little increased activity (median MIC also 16 mg/l). The Bacteroides organisms were highly susceptible to metronidazole and to the hydroxy metabolite, each having a median MIC of 1 mg/l.
The in vitro antibacterial activity of the antifungal compound fenticonazole was compared with those of clotrimazole, miconazole, tetracycline, and metronidazole against 177 strains of bacterial species associated with either bacterial vaginosis (BV) or skin infections by agar dilution MIC determinations. BV-associated Bacteroides isolates of the Bacteroides melahinogenicus-B. oralis group, Gardnerella vaginalis, Mobiluncus spp., and anaerobic, gram-positive cocci were highly susceptible to fenticonazole, clotrimazole, and miconazole; but Bacteroides spp. not associated with BV, Bacteroides ureolyticus and the Bacteroides fragilis group, were resistant. All Bacteroides strains were susceptible to metronidazole, but the susceptibility of G. vaginalis and Mobiluncus spp. varied. Among the skin bacteria, Staphylococcus aureus, coryneforms, and streptococci were highly susceptible to the imidazoles; but Staphylococcus epidernidis strains were generally resistant. This antibacterial activity may give fenticonazole a useful role in the topical treatment of vaginal discharge and in mycotic skin infections that are superinfected with bacteria.
The in-vitro activity of the quinolone derivative pefloxacin was compared with that of three other quinolones, five beta-lactam antibiotics and three aminoglycosides against 367 isolates from hospital patients and from out-patients with genitourinary infections. MIC90 of pefloxacin and norfloxacin for each strain was the same; that of ciprofloxacin was a little lower. All strains except Escherichia coli were resistant to nalidixic acid. Pefloxacin was highly active against Staphylococcus aureus (39 strains; MIC90 1.0 mg/l) and most strains of coagulase-negative staphylococci (56; 4 mg/l), Esch. coli (50; 0.25 mg/l), other enterobacteria (33; 1.0 mg/l) and Pseudomonas aeruginosa 6; 0.25 mg/l). With Bacteroides spp. (total 78; 64 mg/l), the fragilis group (23) and the fusobacteria (19) were resistant, but the melaninogenicus-oralis group (31; range 0.06- greater than 64 mg/l) and B. ureolyticus (22; 0.125- greater than 64 mg/l) gave variable results. Amongst genitourinary isolates, Neisseria gonorrhoeae (15) and Haemophilus ducreyi (34) were sensitive (less than 0.06 mg/l) but Gardnerella vaginalis (25) and Mobiluncus spp. (11) were resistant (32 mg/l). Pefloxacin was more active than ceftazidime, cefotaxime, ceftizoxime, latamoxef and piperacillin against S. aureus and coagulase-negative staphylococci and than gentamicin, tobramycin and amikacin against coagulase-negative staphylococci. No enterobacteria or pseudomonads were resistant to pefloxacin or other quinolones, whereas some were resistant to beta-lactams and aminoglycosides.
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