Biomedical subjects
Publications and source records attributed to H Hof.
In Listeria spp., various fatty acids are produced; by far the most common members are C15 and C17 chain length fatty acids. This pattern is rather similar in all species. At low temperatures, most of the Listeria are able to change the relative composition whereby more of the C15 fatty acids are produced, which could increase the fluidity of the bacterial cell membrane under these conditions.
The new macrolide derivatives such as clarithromycin, roxithromycin and azithromycin have only slightly stronger in vitro antibacterial activity on Listeria monocytogenes than the older derivatives such as erythromycin and spiramycin. In vivo, however, the new macrolides exert a much better therapeutic action on murine listeriosis. Among the new derivatives, clarithromycin is the most active. Azithromycin has one characteristic advantage: it is still active several days after cessation of therapy because of its long half-life. This strong therapeutic activity may be due to the known intracellular accumulation of macrolides in macrophages, which is essential for the eradication of intracellular bacteria such as L. monocytogenes. In spite of the strong intracellular accumulation the effector function of the defense system is not impaired, because the course of infection with a macrolide-resistant strain of L. monocytogenes in mice was not enhanced by macrolide treatment.
Listeria monocytogenes belongs to the group of intracellular bacteria, which means that they reside and multiply within host cells. The protective immunity against such an infection is mediated by cellular immune mechanisms. Whereas the CD8+ T cell population plays a major role therein, the CD4+ T cells are held to be of minor importance in this defence system. Consequently, one can understand that immune suppression with FK 506 which acts primarily on this latter T cell subset, does not interfere with protective immunity of mice infected with L. monocytogenes. We have demonstrated that the drug blocks neither curing of primary infection, nor formation of granulomas, nor induction of cell populations capable of mediating adoptive transfer of immunity, nor expression of pre-existing immunity.
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In order to investigate activation of the innate immune system in murine toxoplasmosis, T- and B-cell-deficient SCID mice and their co-isogenic immunocompetent C.B-17 counterparts were orally infected with a low-virulent strain of Toxoplasma gondii (DX strain). SCID mice developed a fatal necrotizing toxoplasmosis, whereas CD4+ and CD8+ T cells contributing to inflammatory infiltrates conferred resistance to immunocompetent mice. Significant amounts of interferon-gamma (IFN-gamma) were detectable in SCID mice. The most likely source for this cytokine is activated natural killer (NK) cells. In comparison to immunocompetent mice IFN-gamma levels were reduced in cerebrospinal fluid (CSF) and serum of SCID mice at days 7 and 14 of disease. Similar amounts of tumour necrosis factor (TNF) were detected in both strains of mice. In addition, immunohistochemistry showed major histocompatibility complex (MHC) class II antigen expression on SCID and C.B-17 microglial cells and macrophages demonstrating activation of these cells in both strains. However, the up-regulation of MHC class II antigen on microglia was less pronounced in SCID mice, presumably due to reduced levels of IFN-gamma. Interleukin-6 (IL-6) levels in CSF and serum were elevated in both strains and correlated with systemic and intracerebral disease activity. In conclusion, our results demonstrate activation of macrophages and NK cells as the predominant defence mechanisms of the comprised SCID immune system during toxoplasma infection. This implies a major role for the innate immune system during early stages of toxoplasmosis although T cells are necessary to control the infection efficiently.
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Listeria spp. have been isolated from various food items. This fact does not mean in any case a true health risk. A balanced appraisal should be based on quantitative as well as qualitative aspects. Actually, there is still an open debate whether a limited number of Listeria has to be tolerated at least in certain food items. In addition, the pathogenic potency of an isolate may be put into account. Pathogenicity of various Listeria spp. definitely varies. Most Listeria spp., except Listeria monocytogenes, can be regarded as harmless to man. Also, not all strains of L. monocytogenes are pathogenic: rough variants possess only reduced virulence; non-hemolytic mutants have completely lost their pathogenic potency. Furthermore, several other virulence factors may be lost under natural conditions, so that among the majority of hemolytic, pathogenic isolates there may be others which are non-pathogenic or of low virulence only. Unfortunately, these strains actually cannot be recognized and characterized by common laboratory tests, so that animal pathogenicity seems to be the only way to get a final conclusion on the health risk of an isolate of L. monocytogenes from any food. The problem raised by this is which animal test is able to predict a true health risk either for normal hosts or for immunocompromised patients?
In-vitro clarithromycin was more active than erythromycin against Listeria monocytogenes. The antibacterial action was bacteristatic. In normal adult mice infected with a virulent strain of L. monocytogenes clarithromycin was also more active than erythromycin. A rapid decrease in viable count was obtained, which was not achieved with erythromycin. Early treatment resulted in a complete abrogation of an immune response to L. monocytogenes. In immunocompromised, congenitally athymic (nude) mice, only a moderate effect on the bacterial numbers was observed, indicating that even in vivo the activity of the macrolides is bacteristatic.
Antibodies directed against the major secreted protein of Listeria monocytogenes, termed p60, were found more frequently than antilisteriolysin antibodies in sera of listeriosis patients. Anti-p60 antibodies were also identified in all tested sera from healthy individuals. To test whether p60 provides protection against L. monocytogenes, we constructed an attenuated Salmonella typhimurium aroA strain which secretes p60 via the Escherichia coli hemolysin secretion pathway. Application of this Salmonella strain to BALB/c mice prior to an L. monocytogenes infection induced p60 antibodies in these mice and led to a significantly reduced number of viable bacteria in the spleen compared with that in control animals which were primed with the S. typhimurium aroA strain alone.
The heterogeneity of penicillin-binding proteins (PBPs) of five Listeria species was investigated. Similarities in the overall PBP pattern were found between those of L. welshimeri and L. innocua, and between L. ivanovii and L. seeligeri, and all were distinct from the PBPs of L. monocytogenes. In all species, however, the primary target for beta-lactam antibiotics, as identified in L. monocytogenes recently, appeared highly conserved. In addition, the low-Mr PBP 5 was biochemically very similar in all strains and contained identical binding properties to beta-lactam compounds, suggesting that this protein may play an important role. All other PBPs varied considerably in their penicilloyl-peptide pattern, indicating differences in their amino acid sequences.
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Not only viruses but also certain bacteria, fungi as well as protozoa are able to reside and multiply within host cells; some of these microorganisms are facultative, others obligate intracellular hosts. They differ from each other in their mode of entry and in their strategies to survive intracellularly. Some remain in the phagocytic vacuole where they either block the fusion of lysosomes or resist the attack of the acidic milieu as well as the enzymatic digestion and multiply. Others escape from the vacuole to the cytoplasm where they travel around. This implies that chemotherapy has to respect these various intracellular life cycles. Therefore an antibiotic treatment can only be effective when the drug arrives in an active form at the special site of microbial residence.
In vitro practically all common antibiotics except cephalosporins are active against nearly all natural isolates of Listeria monocytogenes; the therapeutic efficacy of antibiotic treatment is, however, rather limited, since up to 30% listeriosis patients will succumb to this infection. At least one reason for this low in vivo efficiency is the intracellular habitat of L. monocytogenes. In animal experiments ampicillin or amoxicillin, respectively, are still the most active drugs. In addition, rifampicin also has pronounced protective activity. Coumermycin, which unfortunately cannot be given to humans, is the most reliable drug in animals.
Various antibiotics were evaluated as to their effect on Listeria monocytogenes SLCC 4013 multiplying within L 929 mouse fibroblast cells. Antibiotics were employed in concentrations above the MIC value. However, there was no measurable effect of some drugs on intracellular listeriae (azlocillin, mezlocillin, cephalothin, ciprofloxacin, chloramphenicol). With other drugs an inhibition of intracellular growth was observed (penicillin, ampicillin, rifampicin, rifapentine, erythromycin, doxycycline, co-trimoxazole, coumermycin). Notably, with none of the antibiotics a complete eradication of the listeriae was achieved. There is a good correlation of these results with animal experiments. Therefore, the cell culture system might be useful for the screening of new antibiotics.
A human isolate of Salmonella typhimurium was found to be highly resistant to several antibiotics including quinolones (MIC of ciprofloxacin 16 mg/l). Killing by ciprofloxacin was only achieved after prolonged exposure to drug concentrations above the MIC. The quinolone resistance of this particular strain was not mediated by plasmids which, however, coded for several other resistance properties.