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PubMed2004

Evolutionary dynamics of insertion sequences in Helicobacter pylori.

Prokaryotic insertion sequence (IS) elements behave like parasites in terms of their ability to invade and proliferate in microbial gene pools and like symbionts when they coevolve with their bacterial hosts. Here we investigated the evolutionary history of IS605 and IS607 of Helicobacter pylori, a genetically diverse gastric pathogen. These elements contain unrelated transposase genes (orfA) and also a homolog of the Salmonella virulence gene gipA (orfB). A total of 488 East Asian, Indian, Peruvian, and Spanish isolates were screened, and 18 and 14% of them harbored IS605 and IS607, respectively. IS605 nucleotide sequence analysis (n = 42) revealed geographic subdivisions similar to those of H. pylori; the geographic subdivision was blurred, however, due in part to homologous recombination, as indicated by split decomposition and homoplasy tests (homoplasy ratio, 0.56). In contrast, the IS607 populations (n = 44) showed strong geographic subdivisions with less homologous recombination (homoplasy ratio, 0.2). Diversifying selection (ratio of nonsynonymous change to synonymous change, >>1) was evident in approximately 15% of the IS605 orfA codons analyzed but not in the IS607 orfA codons. Diversifying selection was also evident in approximately 2% of the IS605 orfB and approximately 10% of the IS607 orfB codons analyzed. We suggest that the evolution of these elements reflects selection for optimal transposition activity in the case of IS605 orfA and for interactions between the OrfB proteins and other cellular constituents that potentially contribute to bacterial fitness. Taken together, similarities in IS elements and H. pylori population genetic structures and evidence of adaptive evolution in IS elements suggest that there is coevolution between these elements and their bacterial hosts.

DNA Transposable Elements↗

PubMed2002

Development of a real-time fluorescence PCR assay for rapid detection of the diphtheria toxin gene.

We developed and evaluated a real-time fluorescence PCR assay for detecting the A and B subunits of diphtheria toxin (tox) gene. When 23 toxigenic Corynebacterium diphtheriae strains, 9 nontoxigenic C. diphtheriae strains, and 44 strains representing the diversity of pathogens and normal respiratory flora were tested, this real-time PCR assay exhibited 100% sensitivity and specificity. It allowed for the detection of both subunits of the tox gene at 750 times greater sensitivity (2 CFU) than the standard PCR (1,500 CFU). When used directly on specimens collected from patients with clinical diphtheria, one or both subunits of the tox gene were detected in 34 of 36 specimens by using the real-time PCR assay; only 9 specimens were found to be positive by standard PCR. Reamplification by standard PCR and DNA sequencing of the amplification product confirmed all real-time PCR tox-positive reactions. This real-time PCR format is a more sensitive and rapid alternative to standard PCR for detection of the tox gene in clinical material.

Corynebacterium diphtheriae↗

PubMed2004

Distribution of serogroups and genotypes among disease-associated and carried isolates of Neisseria meningitidis from the Czech Republic, Greece, and Norway.

The distribution of serogroups and multilocus sequence types (STs) in collections of disease-associated and carried meningococci from the period 1991 to 2000 in three European countries (the Czech Republic, Greece, and Norway) was investigated. A total of 314 patient isolates and 353 isolates from asymptomatic carriers were characterized. The frequency distributions of serogroups and clone complexes differed among countries and between disease and carrier isolate collections. Highly significant differentiation was seen at each housekeeping locus. A marked positive association of serogroup C with disease was evidenced. The ST-11 complex was strongly positively associated with disease; associations for other clone complexes were weaker. The genetic diversity of the clone complexes differed. A single ST dominated the ST-11 clone complex, while the ST-41/44 complex exhibited greater levels of diversity. These data robustly demonstrated differences in the distribution of meningococcal genotypes in disease and carrier isolates and among countries. Further, they indicated that differences in genotype diversity and pathogenicity exist between meningococcal clone complexes.

Carrier State↗

PubMed2005

Direct detection and identification of Mycobacterium tuberculosis and Mycobacterium bovis in bovine samples by a novel nested PCR assay: correlation with conventional techniques.

Mycobacterium tuberculosis and M. bovis infect animals and humans. Their epidemiology in developed and developing countries differs, owing to differences in the implementation of preventive measures (World Health Organization, 1999). Identification and differentiation of these closely related mycobacterial species would help to determine the source, reservoirs of infection, and disease burden due to diverse mycobacterial pathogens. The utility of the hupB gene (Rv2986c in M. tuberculosis, or Mb3010c in M. bovis) to differentiate M. tuberculosis and M. bovis was evaluated by a PCR-restriction fragment length polymorphism (RFLP) assay with 56 characterized bovine isolates. The degree of concordance between the PCR-RFLP assay and the microbiological characterization was 99.0% (P < 0.001). A nested PCR (N-PCR) assay was developed, replacing the PCR-RFLP assay for direct detection of M. tuberculosis and M. bovis in bovine samples. The N-PCR products of M. tuberculosis and M. bovis corresponded to 116 and 89 bp, respectively. The detection limit of mycobacterial DNA by N-PCR was 50 fg, equivalent to five tubercle bacilli. M. tuberculosis and/or M. bovis was detected in 55.5% (105/189) of the samples by N-PCR, compared to 9.4% (18/189) by culture. The sensitivities of N-PCR and culture were 97.3 and 29.7, respectively, and their specificities were 22.2 and 77.7%, respectively. The percentages of animals or samples identified as infected with M. tuberculosis or M. bovis by N-PCR and culture reflected the clinical categorizations of the cattle (P of <0.05 to <0.01). Mixed infection by N-PCR was detected in 22 animals, whereas by culture mixed infection was detected in 1 animal.

Animals↗

PubMed2005

CD46-utilizing adenoviruses inhibit C/EBPbeta-dependent expression of proinflammatory cytokines.

The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-gamma) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1alpha and -beta, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-gamma-induced C/EBPbeta protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-gamma signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.

Adenoviridae↗

PubMed2006

Epidemiology, etiology and pathophysiology of traveler's diarrhea.

Traveler's diarrhea (TD) is the most frequent health problem in travelers to developing countries. Several personal and environmental risk factors are at the basis of TD acquisition and are discussed in this paper. TD is caused by a wide range of infectious organisms, ETEC and EAEC bacteria strains being the main enteropathogens incriminated in TD. Other causative bacteria are: Shigella spp., Campylobacter spp., Vibrio spp., Aeromonas spp., Salmonella spp., and Plesiomonas spp. Parasite species are also included: Cyclospora cayetanensis, Giardia lamblia, Cryptosporidium, Entamoeba histolytica, as well as viruses: rotavirus, adenovirus, Norwalk virus. Due to the great diversity of pathogens incriminated, several pathophysiological mechanisms have been described and some of them are still poorly understood. The clinical symptoms present are also quite variable, although inflammatory and non-inflammatory diarrhea have been established as a classical and basic classification of diarrhea.

Bacteria↗

PubMed2006

Molecular profiling improves diagnoses of rejection and infection in transplanted organs.

The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays, we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or Trypanosoma cruzi infection. We found a set of genes whose expression patterns were typical of acute rejection, and another set of genes that discriminated between rejection and T cruzi infection. These sets revealed acute rejection episodes up to 2 weeks earlier, and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the 2 sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa.

Bacterial Infections↗

PubMed1986

The comparison of myocardial dysfunction in three forms of experimental septic shock.

A rabbit model of septic shock was used to determine if myocardial dysfunction is a common component of shock due to diverse neonatal pathogens, and prostaglandins modulate septic myocardial dysfunction. The infusion of heat-killed Escherichia coli (group I), Haemophilus influenzae (group II), or Staphylococcus epidermidis (group III) produced significant decreases in the first derivative of left ventricular pressure with respect to time (p less than 0.05). Each organism also produced significant changes in mean arterial pressure, cardiac output, and heart rate, while pulmonary artery pressure was altered in groups I and III. Saline-infused control animals (group IV) exhibited no significant changes in any hemodynamic variable. Blood gas variables were not significantly changed in any group. These cardiovascular changes appeared dependent on arachidonic acid metabolism since indomethacin pretreatment prevented the cardiovascular changes induced by bacterial infusion. These results suggest that septic myocardial dysfunction is a common component of gram-negative and gram-positive septic shock, and that myocardial dysfunction is modulated by prostaglandin products.

Animals↗

PubMed2005

Information technologies for vaccine research.

Vaccinology is a combinatorial science which studies the diversity of pathogens and the human immune system, and formulations that can modulate immune responses and prevent or cure disease. Huge amounts of data are produced by genomics and proteomics projects and large-scale screening of pathogen-host and antigen-host interactions. Current developments in computational vaccinology mainly support the analysis of antigen processing and presentation and the characterization of targets of immune response. Future development will also include systemic models of vaccine responses. Immunomics, the large-scale screening of immune processes which includes powerful immunoinformatic tools, offers great promise for future translation of basic immunology research advances into successful vaccines.

Animals↗

PubMed2003

Current diagnosis and treatment of infective endocarditis.

The incidence of infective endocarditis continues to rise with a yearly incidence of around 15,000 to 20,000 new cases in the USA. As a result, rapid diagnosis, effective treatment and prompt recognition of complications are essential to desirable clinical outcomes. Recent guidelines such as the Duke criteria have incorporated echocardiography for diagnosis of infective endocarditis, making this diagnostic test mandatory for patients with suspected infective endocarditis. The diversity of pathogens that can cause infective endocarditis, some of which cannot be cultured easily, makes diagnosis even more difficult. Coagulase-negative staphylococci and viridans streptococci groups continue to be the major causative microorganisms of infective endocarditis. In the case of culture-negative endocarditis or infective endocarditis caused by fastidious microorganisms, the polymerase chain reaction and probe-based diagnostic methods are available to clinical reference laboratories.

Endocarditis, Bacterial↗

PubMed1991

Differences in the two-dimension-gel electrophoresis protein patterns of the lethal K and benign B variants of encephalomyocarditis virus.

Variants of encephalomyocarditis virus (EMCV) are indistinguishable by hyperimmune serum. In spite of their antigenic similarity, they produce different disease syndromes in susceptible strains of mice. To understand the basis for the diversity in pathogenicity, studies have been initiated to characterize each of the virus variants. In this study, two-dimensional gel electrophoresis was used to compare the proteins produced by the benign EMCV-B with those produced by lethal EMCV-K. The data show that (i) the replication cycle of each of the virus variants is characteristic of picornaviruses, (ii) the VP1 of EMCV-K is more basic than that of EMCV-B, and (iii) three proteins, one a major component of VP1, the other two with molecular weight of about 12,000, are present in EMCV-K but not in EMCV-B.

Electrophoresis, Gel, Two-Dimensional↗

PubMed2003

A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62.

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-alpha, IL-6, and IFN-gamma) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-alpha and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of "tolerance." ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

Adjuvants, Immunologic↗

PubMed2004

Organism-specific neutrophil-endothelial cell interactions in response to Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus.

The recruitment of polymorphonuclear leukocytes (PMNs) from the vascular space into the lung interstitium and airspace is an early step in the host innate immune response to bacterial invasion of these sites. To determine the ability of intact bacteria to directly elicit PMN migration across an endothelial monolayer, we studied in vitro migration of PMNs across a monolayer of human pulmonary microvascular endothelial cells in response to Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli, as well as to purified E. coli LPS. Bacterial induction of PMN migration was dose dependent and elicited by > or =10(4) bacteria/ml of each of the species tested. Pretreatment of PMNs with blocking Abs to CD18 significantly inhibited migration of PMN in response to all stimuli tested, but had the most profound effect on migration to S. pneumoniae and S. aureus. Intact E. coli were 10 times more potent in inducing transmigration of PMNs than a corresponding amount of purified LPS. Bacterial induction of PMN migration did not correlate with up-regulation of surface endothelial ICAM-1 expression (purified LPS >> intact E. coli > S. aureus and S. pneumoniae) nor up-regulation of VCAM-1 and E-selectin. Neutralizing Ab to ICAM-1 had no effect on PMN migration to any of the bacteria or to purified LPS. These findings demonstrate that diverse bacterial pathogens induce PMN migration across a pulmonary microvascular endothelial cell monolayer in a fashion that appears to be organism specific. In addition, intact bacteria elicit PMN-endothelial cell interactions distinct from those seen when purified bacterial products are used as agonists.

Adult↗

PubMed2002

The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.

The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.

Animals↗

PubMed1999

Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1.

IFN-gamma activates macrophages to kill diverse intracellular pathogens, but does not activate human macrophages to kill virulent Mycobacterium tuberculosis. We tested the hypothesis that this is due to inhibition of IFN-gamma signaling by M. tuberculosis and found that M. tuberculosis infection of human macrophages blocks several responses to IFN-gamma, including killing of Toxoplasma gondii and induction of FcgammaRI. The inhibitory effect of M. tuberculosis is directed at transcription of IFN-gamma-responsive genes, but does not affect proximal steps in the Janus kinase-STAT pathway, as STAT1alpha tyrosine and serine phosphorylation, dimerization, nuclear translocation, and DNA binding are intact in M. tuberculosis-infected cells. In contrast, there is a marked decrease in IFN-gamma-induced association of STAT1 with the transcriptional coactivators CREB binding protein and p300 in M. tuberculosis-infected macrophages, indicating that M. tuberculosis directly or indirectly disrupts this protein-protein interaction that is essential for transcriptional responses to IFN-gamma. Gamma-irradiated M. tuberculosis and isolated cell walls reproduce the effects of live bacteria, indicating that the bacterial component(s) that initiates inhibition of IFN-gamma responses is constitutively expressed. Although lipoarabinomannan has been found to exert effects on macrophages, it does not account for the inhibitory effects of cell walls. These results indicate that one mechanism for M. tuberculosis to evade the human immune response is to inhibit the IFN-gamma signaling pathway, and that the mechanism of inhibition is distinct from that reported for Leishmania donovani or CMV, in that it targets the interaction of STAT1 with the basal transcriptional apparatus.

Animals↗

PubMedDate not supplied

[Prevention of wasting and opportunistic infections in HIV-infected patients in West Africa: a realistic and necessary strategy before antiretroviral treatment].

The medical inequalities between countries of the North and South (infrastructure, drug availability, medical techniques) are particularly marked in terms of the challenge posed by HIV infection. We propose a strategy for monitoring adult patients in West Africa that is appropriate to the situation in the field and to economic constraints. The aim of this strategy is to increase the quality of life and the life expectancy of HIV-infected adults and to prevent the overcrowding of hospital departments with patients in the terminal phase of AIDS. We analyzed the biological and clinical spectrum of HIV infection before the onset of the diseases that define AIDS (excluding pulmonary tuberculosis). We found that it was particularly important to diagnose B-stage diseases early, especially atypical chronic cutaneous and mucous diseases. Careful analysis of data from a routine hemogram (total lymphocyte count 2500/ml; paradoxical eosinopenia), even in the absence of a CD4 lymphocyte count, should also enable clinicians from a wide variety of health structures to identify the HIV-infected patients most likely to benefit from more detailed clinical follow up, prophylaxis of opportunistic infections using cotrimoxazole, nutritional checkups and prevention of wasting. Cachexia is the most common AIDS-associated disease in West African patients. It involves an overall decrease in calorific intake, diarrhea, immune system activation, an increase in TNFalpha production and greater energy expenditure when resting. Recent nutritional studies have shown that it is vital to optimize the calorific intake of HIV-infected patients presenting with chronic diarrhea, before the onset of severe immune deficiency, to prevent wasting. So, spontaneous calorific intake should de routinely determined in HIV-infected patients and an optimal diet provided. Specific training in nutrition is required for doctors and nurses, as is consideration of the logistic organization required to provide nutritional support to HIV-infected adults. Despite the large number of individuals infected and the lack of sophisticated paraclinical facilities, we feel that it is possible to establish rational management "a minima" of HIV infection in West Africa, whilst waiting for antiretroviral drugs to become more widely available. This strategy could be of direct benefit to patients without swallowing up the financial resources of the health system in expensive biological follow up. Such basic management is also required before the new antiretroviral drugs become widely available. Research should be carried out in parallel in several reference centers in West Africa to determine the most effective associations of antiretroviral drugs and the optimal timing of treatment during the course of infection and to assess the potential side effects of these drugs in HIV patients exposed to recurrent antigenic stimulation by a wide diversity of pathogens.

AIDS-Related Opportunistic Infections↗

PubMed2001

[Introduction of ongoing research projects on echinococcosis at Asahikawa Medical College and some comments on the surveillance, prevention and control of alveolar echinococcosis in Japan].

All researchers working at Department of Parasitology, Asahikawa Medical College (AMC) have been involved in either basic or applied research on echinococcosis (alveolar echinococcosis; AE, cystic echinococcosis; CE) and neurocysticercosis (NCC). As these parasitic diseases are 1) most serious helminthic infections threatening human life, 2) caused by the larval stage of very closely related taeniid cestodes and 3) recognized as global emerging parasitic diseases, we have to establish research reference center for differentiation of these diseases, since the recommendations for the treatment of these three diseases differ critically. We at AMC have already established highly reliable differential serodiagnosis for these all using native antigens and recombinant antigens for AE and NCC. Based on such scientific contribution, we have been involved in many international collaboration projects on AE, CE and NCC in Asia, Europe, Africa and America. Basic research from mitochondrial DNA analysis of Echinococcus multilocularis (causative agent of AE) and Taenia solium (NCC) has revealed and/or implied the origin of the polymorphism of these parasites in the world and diversity of pathogenicity. Epidemiological surveillance of AE in China has strongly suggested that the risk factor is dog carer but not dog feces, dog owned, wild herbs or fox hunting. As the ongoing serology in Hokkaido carried out by the Hokkaido Institute of Public Health is for the primary screening of AE, it is impossible to identify AE patients. It is, therefore, recommended that serology for identification of AE without surgical confirmation is the key to be introduced for differentiation of AE patients, either asymptomatic or symptomatic, in order to recognize the incidence of AE in Hokkaido. Without the true incidence of AE, it is impossible to establish any reliable systems for the surveillance, prevention and control of AE in Hokkaido, Japan.

Echinococcosis↗

PubMed2001

[Acute infectious myelitis].

BACKGROUND: Acute myelitis is a clinical condition affecting the motor, sensor or autonomic function of the spinal cord. The etiology is often unknown, although a diversity of pathogens have been associated with acute myelitis. MATERIALS AND METHODS: Based on relevant literature we present an overview of the most important pathogens responsible for infectious acute myelitis in northern Europe, as well as recommendations regarding diagnostic guidelines. RESULTS: The pathogenic mechanisms are only partly known. Both replication of the pathogen, cellular defence mechanisms after invasion of the central nervous system, and the immune system seem to be important for the neurological damage. INTERPRETATION: Identification of a causative agent is important for the etiologic diagnosis and offers the possibility of specific treatment.

Acute Disease↗