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PubMed2000

Genes that fight infection: what the Drosophila genome says about animal immunity.

From deciphering the principles of heredity to identifying the genes that control development, the fruit fly Drosophila melanogaster is being used to deconstruct an increasing number of biological processes. Genetic studies of Drosophila responses to microbial infection have identified regulators of innate immunity that are functionally conserved in mammals. These recent findings highlight the ancient origins of animal immune responses and demonstrate the potential of Drosophila for dissecting host-pathogen interactions. The sequencing of the Drosophila genome both enhances genetic approaches and provides new clues for the identification of key components of innate immunity. This article summarizes how information gained from genomic analysis contributes to our understanding of how animals cope with infectious disease.

Adaptation, Physiological↗
PubMed2000

Steroid hormone regulation of antiviral immunity.

Recent observations in both humans and animals have demonstrated that stress is immunomodulatory and can alter the pathogenesis of microbial infections to the extent that it may be adverse to health. Stress disrupts homeostasis, and the body responds through endocrine and nervous system interactions in an effort to re-establish the health of the host. However, the resulting physiologic changes associated with stress, such as the rise in serum glucocorticoids (GCs), are implicated in suppression of antiviral immunity. Therefore, it would be of significance to counterregulate stress-mediated immunosuppression during viral infection to improve immune responses and limit virus-mediated damage. The data in this study focus upon the antiglucocorticoid influence of a native steroid hormone that has been shown to augment immune function and protect animals against lethal viral infections. Androstenediol (5-androstene-3 beta,17 beta-diol, AED), a metabolite of dehydroepiandrosterone (DHEA), confers protection against lethal infection with influenza A virus. The protective activity appears to counterbalance the function of the regulatory GCs because AED prevents GC-mediated suppression of IL-1, TNF-alpha, and IL-2 secretion. Furthermore, AED inhibits GC-induced transcription of a GC-sensitive reporter gene.

Animals↗
PubMed1996

An Experimental Test of the Rhizopine Concept in Rhizobium meliloti.

In some Rhizobium-legume symbioses, compounds known as rhizopines are synthesized by bacteroids and subsequently catabolized by free-living cells of the producing strain. It has been suggested than rhizopines act as proprietary growth substrates and enhance the competitive ability of the producing strain in its interactions with the diverse microbial community found within the rhizosphere. Wild-type, rhizopine-producing Rhizobium meliloti L5-30 and mutant L5-30 strains deficient for either rhizopine synthesis or catabolism were inoculated onto lucerne host plants in competition experiments. These experiments demonstrated that no apparent advantage resulted from the ability to synthesize a rhizopine, whereas the ability to catabolize rhizopine provided a clear advantage when an organism was in competition with a strain without this ability. The results suggest that when an organism is in competition with a catabolism-deficient mutant, the ability to catabolize rhizopine results in enhanced rates of nodulation. The results of the experiments were not consistent with the hypothesis that the sole role of rhizopines is to act as proprietary growth substrates for the free-living population of the producing strain.

Journal Article↗
PubMed1997

Invasion and persistence of Salmonella in human fibroblasts positive or negative for endogenous HLA B27.

OBJECTIVE: Analysis of the interaction of enteropathogenic bacteria with HLA B27 transfected murine fibroblasts showed a specific influence of HLA B27 on microbial invasiveness. This possible novel mechanism for the action of HLA B27 should be verified by using endogenous HLA B27 positive and negative human fibroblasts as a model for the direct interaction of arthritogenic bacteria and host cells. METHODS: Fibroblasts were obtained from healthy donors positive or negative for HLA B27; cultivated as monolayers; and infected with Salmonella enterica serovar enteritidis. RESULTS: Invasion and survival of bacteria in human cells was not influenced by the presence of HLA B27. Enhancement of HLA class I molecule expression by treatment of cultures with interferon gamma decreased invasion and survival of bacteria in both HLA B27 positive and negative cells. After disappearance of live bacteria lipopolysaccharide antigens persisted within cells. CONCLUSION: Endogenous HLA B27 does not modulate the direct interaction of Salmonella with human cells. Non-professional phagocytes are able to limit bacterial survival in cells, and interferon gamma accelerates killing of bacteria, but arthritogenic antigens persist after disappearance of live bacteria.

Analysis of Variance↗
PubMedDate not supplied

[Colonial organization and intercellular communication of microorganisms].

This review covers the modern concepts and recent data demonstrating the integrity and coherence of microbial populations (colonies, biofilms, etc.) as peculiar "super-organisms." Special attention is given to such relevant phenomena as apoptosis, bacterial altruism, quorum effects, collective differentiation of microbial cells, and the formation of population-level structures such as an extracellular matrix. Emphasis is placed on the channels in colonies and agents of intercellular communication in microbial populations. The involvement of a large number of evolutionarily conserved communicational facilities and patterns of intercellular interactions is underscored. Much attention is also given to the role of colonial organization and intercellular communication in parasite/commensal/symbiont-multicellular host organism systems.

Apoptosis↗
PubMed2001

Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles.

The aim of antibacterial chemotherapy is to achieve sufficient drug concentrations at the site of infection for an adequate length of time to ensure bacterial eradication and optimize clinical success. Whether the desired outcome is achieved or not depends on a number of pathogen-, drug- and patient-related factors. Neither microbiologic activity nor antibacterial pharmacokinetic data alone can adequately describe the complex interaction between pathogen, host and antibacterial during the disease process. A relatively new discipline - pharmacodynamics - seeks to integrate both microbiologic and pharmacokinetic data. The particular model that best predicts clinical outcome depends on the pattern of microbial killing and the persistence of antibacterial effects after plasma concentrations have fallen below the minimum inhibitory concentration (MIC) for the target pathogen (post-antibiotic effect [PAE]). The beta-lactams, for example, exhibit time-dependent bacterial killing with minimal persistent effects. Time above MIC (T(MIC)) is therefore the parameter that best correlates with clinical efficacy for these agents and that, in turn, necessitates multiple daily dosing to optimize the duration of exposure. The macrolides erythromycinA and clarithromycin exhibit a similar pharmacokinetic/pharmacodynamic relationship to that of the beta-lactams, although for clarithromycin the area under the concentration-time curve (AUC) also correlates with clinical outcome (reflecting the more prolonged PAE of this agent). Azithromycin, ketolides, such as telithromycin (HMR 3647), streptogramins and fluoroquinolones exhibit concentration-dependent killing and have prolonged persistent effects, such that the AUC:MIC or Cmax:MIC ratio correlates most closely with clinical efficacy. For these agents the aim is to maximize drug concentrations to which the target pathogen is exposed and this may require higher doses and hence enable longer dosing intervals to be used. In summary, pharmacodynamic models provide a unique approach to determining likely in vivo activity of individual antibacterial agents and prediction of clinical outcomes.

Animals↗
PubMed2005

Interaction of pathogenic fungi with host cells: Molecular and cellular approaches.

This review provides an overview of several molecular and cellular approaches that are likely to supply insights into the host-fungus interaction. Fungi present intra- and/or extracellular host-parasite interfaces, the parasitism phenomenon being dependent on complementary surface molecules. The entry of the pathogen into the host cell is initiated by the fungus adhering to the cell surface, which generates an uptake signal that may induce its cytoplasmatic internalization. Furthermore, microbial pathogens use a variety of their surface molecules to bind to host extracellular matrix (ECM) components to establish an effective infection. On the other hand, integrins mediate the tight adhesion of cells to the ECM at sites referred to as focal adhesions and also play a role in cell signaling. The phosphorylation process is an important mechanism of cell signaling and regulation; it has been implicated recently in defense strategies against a variety of pathogens that alter host-signaling pathways in order to facilitate their invasion and survival within host cells. The study of signal transduction pathways in virulent fungi is especially important in view of their putative role in the regulation of pathogenicity. This review discusses fungal adherence, changes in cytoskeletal organization and signal transduction in relation to host-fungus interaction.

Cell Adhesion↗
PubMed1980

Injury of respiratory epithelium.

The large surface area provided by the respiratory tract epithelium of humans for exposure to microbial agents and toxic substances in the environment makes this organ system very vulnerable but a good early indicator of adverse health effects. However, the complexity of pulmonary defense mechanisms complicates definition of the interactive effects of pollutants and infectious agents. Tracheal organ culture has been utilized to maintain organized, differentiated respiratory epithelium in vitro. This model system permits the exposure of respiratory epithelium to injurious agents in an easily visualized and controlled environment. Effects of individual toxin and/or infectious agents may be examined without the involvement of most host defenses and unwanted secondary microbial invaders which hamper interpretation of in vivo model studies. Further, elements of host immune response, pharmacologic agents and the like may be added selectively if desired. A body of information is being developed on specialized respiratory cell injury by various common pathogenic agents--including respiratory syncytial virus, parainfluenza virus type 3, Bordetella pertussis and Mycoplasma pneumoniae--through studies in tracheal organ cultures. These agents injure specialized epithelial cells in different ways, providing a spectrum of changes against which the added effects of toxic substances could be evaluated at the cellular and subcellular levels. Information on the pathogenesis of infectious/toxic injury could suggest new directions for human health research and for means to benefit the human host.

Animals↗
PubMed1985

Subdivision of Mycobacterium tuberculosis for epidemiological purposes: a seven year study of the "Classical' and 'Asian' types of the human tubercle bacillus in South-East England.

Human strains of Mycobacterium tuberculosis were divided into the 'Classical' and 'Asian' types according to their sensitivity to thiophen-2-carboxylic acid hydrazide. The isolation of these two types in South-East England was studied during a seven-year period (1977-1983). The 'Asian' type was more prevalent among ethnic Asian patients than among ethnic Europeans. Among Europeans there was a decline in the isolation rate of 'Classical' strains and a small but significant increase in 'Asian' strains during the study period, so that the proportion of the latter type in this group is increasing. The type of bacillus was unrelated to the site of isolation except that the incidence of lymphadenitis due to the 'Asian' type among European females was significantly higher than expected. In general, European patients tended to be older than Asian patients, and the differences in age distribution according to site of isolation and type of bacillus in each ethnic group were small. A notable exception occurred with European females infected with the 'Asian' type, whose age distribution was similar to the Asians. In view of the differences in behaviour of the two types of human tubercle bacilli in this country there is a need to continue a bacteriological surveillance and also to determine whether the nature of the host-pathogen interaction varies according to the type of bacillus.

Adolescent↗
PubMed2000

Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens.

This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen intermediates (RNI) in mammalian immunity. Reflections on redundancy in immunity help explain an apparent paradox: the phagocyte oxidase and inducible nitric oxide synthase are each nonredundant, and yet also mutually redundant, in host defense. In combination, the contribution of these two enzymes appears to be greater than previously appreciated. The remainder of this review focuses on a relatively new field, the basis of microbial resistance to RNI. Experimental tuberculosis provides an important example of an extended, dynamic balance between host and pathogen in which RNI play a major role. In diseases such as tuberculosis, a molecular understanding of host-pathogen interactions requires characterization of the defenses used by microbes against RNI, analogous to our understanding of defenses against reactive oxygen intermediates. Genetic and biochemical approaches have identified candidates for RNI-resistance genes in Mycobacterium tuberculosis and other pathogens.

Animals↗
PubMed2002

What is a pathogen?

The question 'what is a pathogen?' derives from pathogen-centered views of microbial pathogenesis that invoke microbial characteristics to explain virulence. However, virulence cannot be an independent microbial variable since it is only expressed in a susceptible host. Hence, the question 'what is a pathogen?' cannot be separated from the question 'what is a host?' Given that virulence is an outcome of the host-microbe interaction that is not invariant from host to host, neither the pathogen or the host can be defined independently. To sidestep this paradox, one can focus on the outcome of the interaction using host damage as the common denominator to define and explain the various outcomes that can result from the host-microbe interaction. Using this concept a pathogen is defined as a microbe capable of causing host damage.

Animals↗
PubMed2004

Transcription profile of Helicobacter pylori in the human stomach reflects its physiology in vivo.

BACKGROUND: Little is known about levels of expression of Helicobacter pylori genes in the human host. We therefore developed a quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) assay to measure transcript profiles of H. pylori in the human stomach. METHODS: In vivo expression of 16 genes on the cag pathogenicity island and of 18 putative virulence genes was quantitated by isolation of total RNA directly from infected human gastric mucosa. The results were compared with in vitro expression determined from H. pylori cells grown in culture. RESULTS: The highest levels of expression were found for cag1 and cag25 and for genes, such as urease and catalase, that may be important for bacterial homeostasis in the relatively hostile environment of the gastric mucosa. Transcript abundance, relative to 16S rRNA, was lower in vivo than in vitro, which suggests that H. pylori cells are in stationary phase in the gastric environment. This was particularly apparent for cagA. Since CagA is arguably of unique importance, in terms of interaction with the host, tight control of its in vivo expression might be particularly important. CONCLUSIONS: qRT-PCR is a powerful tool to measure gene expression in human or animal tissue that contains minute amounts of microbial mRNA, and the results reflect on the physiology of the pathogen in its natural host.

Adult↗
PubMed2002

The promise of structural genomics in the discovery of new antimicrobial agents.

Structural Genomics stands out among the emerging fields of proteomics since it influences the drug discovery process at so many points. Recent developments in protein expression technologies, x-ray crystallography and NMR spectroscopy provide the essential elements for high-throughput structure determination platforms. Bioinformatics methods to interrogate the resulting data will provide comprehensive, genome-wide databases of protein structure. Genomic sequencing and methods for high-throughput expression and protein purification are furthest advanced for microbial genes and so these have been the early targets for structural genomics initiatives. The information will be invaluable in understanding gene function, designing broad-spectrum small molecule inhibitors and in better understanding drug-host interactions.

Anti-Bacterial Agents↗
PubMed2001

[Biological effects of microorganisms, their substances and immunosuppressive agents in mice].

The author provide evidence from several aspects that the normal microbial flora has a permanent and life-long immune modulating role in conventional organisms and a stimulating effect both on specific and non-specific defence. However, in case of artificial interventions (stress, drugs) affecting the organism, existence of the normal flora may have an adverse effect (endotoxin effect, bacterial translocation). The immunomodulants show a stimulating affect mainly in organisms with undeveloped immune system, and their effects are independent from the presence or absence of the microbial flora. With ageing, effect of immunomodulants can change and become indifferent or even suppressive. Dose-dependence of stimulating or suppressing effect of immunomodulants may be related to their non-immunological effects (endotoxin effect, bacterial translocation). Finally, on the basis of the results, the authors consider the germfree mouse suitable for examining the effect of a given agent in the practice, on one hand, and for observing the host organism's reactions, free from the influence of the normal microbial flora, on the other. Along with the known physiological and pathological events, the results draw also attention to as distant fields as drug sensitivity, drug interactions influencing drug sensitivity. The author put emphasis on importance of germfree environment during immunosuppressive treatments in humans and when making special examinations under experimental conditions.

Aging↗
PubMed1998

Biological effects of microorganisms and their substances in mice.

In our experiments we evidence from several aspects that the normal microbial flora has a permanent and life-long immune modulating role in conventional organisms and a stimulating effect both on specific and non-specific defense. However, in case of artificial interventions (stress, drugs) affecting the organism, existence of the normal flora may have an adverse effect on it (endotoxin effect, bacterial translocation). The immunomodulants show a stimulating effect mainly in organisms with undeveloped immune system, and their effects are independent from the presence or absence of the microbial flora. With ageing, effect of immunomodulants can change and become indifferent or even suppressive. Dose-dependence of stimulating or suppressing effect of immunomodulants may be related to their non-immunological effects (endotoxin effect, bacterial translocation). Finally, on the basis of our experiments, we consider the Gf mouse suitable for examining the effect of a given agent in the practice, on the one hand, and for observing the host organism's reactions, free from the influence of the normal microbial flora, on the other. Along with the known physiological and pathological events, our results draw also attention to as distant fields as drug sensitivity, drug interactions influencing drug sensitivity. The authors put emphasis on importance of germfree environment during immunosuppressive treatments in humans and when making special examinations under experimental conditions.

Animals↗
PubMed1998

Role of the clinical microbiology laboratory in the diagnosis of infections.

The proper use and interpretation of clinical microbiology test results may be complicated but critical to the care of cancer patients. The microbiology laboratory director is often available to offer advice concerning the differential diagnosis, choice of specimens, as well as the optimal stains and cultures to facilitate diagnosis. Additionally, the rapid interpretation of Gram-stained smears provides useful, occasionally lifesaving, information relative to the etiologic diagnosis and empiric antimicrobial therapy. The microbiology laboratory director should also provide further interpretation of culture and antimicrobial testing results that allow the clinical service to focus on the most critical data. Person-to-person or telephone conversations discussing important laboratory information should be followed up by a written summary report placed in the patient's chart so all services involved share the same interpretation (Figure 2). The clinical service has an important responsibility to communicate with the laboratory to optimize care of the patient with cancer. The laboratory compiles data collected from groups of patients that is available and useful to physicians. Review and discussion of test utilization is essential for cost-effective, quality health care. This may include analysis of blood cultures documenting an acceptable level of contamination, appropriate number collected per day, and sufficient blood volume per culture. In addition, information about changing resistance patterns or nosocomial transmission can be provided to the clinician. As patients with malignancies become more complex and their infections increasingly difficult to treat, regular interaction between the laboratory and clinician is likely to improve patient care.

Diagnosis, Differential↗