Biomedical subjects

C Anthony Hart

Publications and source records attributed to C Anthony Hart.

At least 19 recordsLinked to original sources

PubMed2005

Bacteremia among children admitted to a rural hospital in Kenya.

BACKGROUND: There are few epidemiologic data on invasive bacterial infections among children in sub-Saharan Africa. We studied every acute pediatric admission to a rural district hospital in Kenya to examine the prevalence, incidence, types, and outcome of community-acquired bacteremia. METHODS: Between August 1998 and July 2002, we cultured blood on admission from 19,339 inpatients and calculated the incidence of bacteremia on the basis of the population served by the hospital. RESULTS: Of a total of 1783 infants who were under 60 days old, 228 had bacteremia (12.8 percent), as did 866 of 14,787 children who were 60 or more days of age (5.9 percent). Among infants who were under 60 days old, Escherichia coli and group B streptococci predominated among a broad range of isolates (14 percent and 11 percent, respectively). Among infants who were 60 or more days of age, Streptococcus pneumoniae, nontyphoidal salmonella species, Haemophilus influenzae, and E. coli accounted for more than 70 percent of isolates. The minimal annual incidence of community-acquired bacteremia was estimated at 1457 cases per 100,000 children among infants under a year old, 1080 among children under 2 years, and 505 among children under 5 years. Of all in-hospital deaths, 26 percent were in children with community-acquired bacteremia. Of 308 deaths in children with bacteremia, 103 (33.4 percent) occurred on the day of admission and 217 (70.5 percent) within two days. CONCLUSIONS: Community-acquired bacteremia is a major cause of death among children at a rural sub-Saharan district hospital, a finding that highlights the need for prevention and for overcoming the political and financial barriers to widespread use of existing vaccines for bacterial diseases.

Bacteremia↗

PubMed2005

Increasing prevalence of multidrug-resistant non-typhoidal salmonellae, Kenya, 1994-2003.

Over the last decade there has been a steady increase in the proportion of multidrug resistance among non-typhoidal salmonellae (NTS) isolated from adult patients with bacteraemia in Kenya. The prevalence of NTS multiply resistant to all commonly available drugs including ampicillin, streptomycin, co-trimoxazole, chloramphenicol and tetracycline rose from 31% in 1994 to 42% at present, with concomitantly higher MICs of each drug. Resistance is encoded on large self-transferable 100-110 kb plasmids. Pulsed field gel electrophoresis of XbaI and SpeI digested chromosomal DNA revealed three main digest patterns for Salmonella enterica serotype Typhimurium and two main patterns for Salmonella enterica serotype Enteritidis. Although the genotypes of NTS remained fairly stable over the last decade, the large increase in MICs of all commonly used drugs and increased MICs of ciprofloxacin, poses a major challenge for treatment of invasive NTS infection.

Adult↗

PubMed2005

Prognostic value of procalcitonin in children with meningococcal sepsis.

OBJECTIVE: To compare procalcitonin, lactate, and C-reactive protein as prognostic markers in children with meningococcal septic shock. DESIGN: Prospective observational study. SETTING: Alder Hey Children's Hospital, Liverpool, UK. PATIENTS: Children admitted to our hospital during a 16-month period with a diagnosis of meningococcal sepsis. RESULTS: Plasma procalcitonin at admission was significantly higher in children with septic shock (median, 73.80 vs. 16.44 ng/mL), those requiring ventilation (median, 47.02 vs. 12.00 ng/mL), and those with a duration of hospital stay >10 days (median, 131.35 vs. 19.26 ng/mL). Both procalcitonin and lactate reliably discriminated between those children with septic shock (area under the curve [AUC] = 0.85 and 0.84, respectively) and durations of hospital stay exceeding 10 days (AUC = 0.87 and 0.79, respectively) and those without, but C-reactive protein did not. Procalcitonin alone reliably discriminated between those children requiring ventilation and those who did not (AUC = 0.72). CONCLUSION: Procalcitonin is a reliable prognostic marker of septic shock, requirement for ventilation, and prolonged hospital stay in children with meningococcal sepsis and performs better than lactate and C-reactive protein.

C-Reactive Protein↗

PubMed2004

Dual infection of infants by human metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis.

The association between severe bronchiolitis and dual infection by human metapneumovirus (hMPV) and human respiratory syncytial virus (hRSV) was investigated in <2-year-old infants with bronchiolitis who were admitted to the hospital during the 2001-2002 winter season. hMPV in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). hRSV was detected in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage by enzyme immunoassay, tissue culture, and RT-PCR. Dual infection with hMPV and hRSV confers a 10-fold increase in relative risk (RR) of admission to a pediatric intensive-care unit for mechanical ventilation (RR, 10.99 [95% confidence interval, 5.0-24.12]; P<.001, by Fisher exact test). Dual infection by hMPV and hRSV is associated with severe bronchiolitis.

Bronchiolitis, Viral↗

PubMed2004

Proinflammatory cytokines and chemokines in humans with Japanese encephalitis.

BACKGROUND: Japanese encephalitis virus (JEV), the mosquito-borne flavivirus, annually causes an estimated 35,000-50,000 encephalitis cases and 10,000-15,000 deaths in Asia, and there is no antiviral treatment. The role played by the immune response in determining the outcome of human infection with JEV is poorly understood, although, in animal models of flavivirus encephalitis, unregulated proinflammatory cytokine responses can be detrimental. METHODS: We studied the innate, cellular, and humoral immune responses in 118 patients infected with JEV, of whom 13 (11%) died. RESULTS: Levels of interferon (IFN)- alpha , the proinflammatory cytokine interleukin (IL)-6, and the chemokine IL-8 were all higher in the cerebrospinal fluid (CSF) of the nonsurvivors than of the survivors (P=.04, P=.006, and P=.04, respectively), as were both the IL-6 : IL-4 ratio in CSF (a marker of the balance of pro- and anti-inflammatory cytokines) and the level of the chemokine RANTES (regulated on activation, normally T cell expressed and secreted) in plasma (P=.03). In contrast, levels of immunoglobulin (Ig) M and IgG in CSF and of IgM in plasma were higher in the survivors (P=.035, P=.003, and P=.009, respectively). Levels of IFN- gamma and nitric oxide did not vary with outcome. CONCLUSIONS: During JEV infection, elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome, but whether they are simply a correlate of severe disease or contribute to pathogenesis remains to be determined.

Adolescent↗

PubMed2004

Sequence divergence in type III secretion gene clusters of the Burkholderia cepacia complex.

The Burkholderia cepacia complex (BCC) comprises a group of bacteria associated with opportunistic infections, especially in cystic fibrosis patients. B. cenocepacia J2315, of the transmissible ET12 lineage, contains a type III secretion (TTS) gene cluster implicated in pathogenicity. PCR and hybridisation assays indicate that the TTS gene cluster is present in all members of the BCC except B. cepacia (formerly genomovar I). The TTS gene clusters of B. cenocepacia J2315 and B. multivorans are similar in organisation but have variable levels of gene identity. Nucleotide sequence data obtained for the equivalent region of the B. cepacia genome indicate the absence of TTS structural genes due to a rearrangement likely to involve more than one step.

Bacterial Proteins↗

PubMed2004

Detection of elements of the staphylococcal cassette chromosome (SCC) in a methicillin-susceptible (mecA gene negative) homologue of a fucidin-resistant MRSA.

OBJECTIVES: To determine the DNA relatedness of an outbreak of community-acquired fucidin-resistant methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) isolated from intravenous drug users (IVDUs). MATERIALS AND METHODS: Relatedness was determined by PFGE analysis of macro-restricted chromosome, together with a variety of PCR methods, to determine polymorphisms in the accessory gene regulator (agr) locus, the structure of the staphylococcal cassette chromosome (SCCmec) and the presence or absence of the gene encoding Panton-Valentine leucocidin (PVL). RESULTS: Clonality of the MRSA and MSSA was established by PFGE, a finding further supported by agr analysis. By PCR, the MRSA contained the typical genetic organization of SCCmec type-1. However, the MSSA, though mecA-negative, contained certain fragments of the SCC. Genes encoding PVL were not detected. CONCLUSIONS: This outbreak involved a community-acquired fucidin-resistant MRSA and its methicillin-susceptible homologue. The MSSA did not contain the mecA gene but did contain elements of the mobile type-I SCC. The MSSA were associated with a change in PFGE pattern with a deletion in fragment size of approximately 215-195 kb.

Bacteremia↗

PubMed2004

Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is the most prevalent acute wheezing disorder in infants and is associated with recurrent wheeze and asthma in childhood. Interleukin 9, a type 2 cytokine has been proposed as a key cytokine in susceptibility to asthma. We aimed to investigate whether interleukin 9 was produced in the lungs of infants with severe RSV disease and if found, from which cells it originated. METHODS: We did 150 non-bronchoscopic bronchoalveolar lavages during the course of ventilation in 24 term infants and 21 preterm infants ventilated for RSV bronchiolitis. We also did 10 bronchoalveolar lavages on the day of intubation in 10 control infants ventilated for non-respiratory causes. We measured pulmonary interleukin 9 mRNA and protein in samples from all groups. We used immunostaining to identify the cells that produce interleukin 9. FINDINGS: Interleukin 9 mRNA expression, which persisted over the course of ventilation, was noted in all infants with bronchiolitis. Three of the control group also showed interleukin 9 mRNA expression. Median interleukin 9 protein concentration on day 1 (1.9 microg/L [range 0.1-36.2]) was significantly greater in term infants with bronchiolitis than either preterm infants (0.4 microg/L [0.1-2.9]; p<0.05) or the control group (0.7 microg/L [0.4-2.5]; p<0.05). There was a trend for interleukin 9 protein concentrations in term, but not preterm infants to decrease over time. Immunostained cell smears showed that most interleukin 9 expression in bronchoalveolar lavage was by neutrophils. INTERPRETATION: In term infants with RSV bronchiolitis, we noted large amounts of interleukin 9 mRNA and interleukin 9 protein. Neutrophils seem to be the main source of this type 2 cytokine. Interleukin 9 production by neutrophils may contribute to the pathogenesis of RSV disease. These findings may be relevant to other disease processes in the lung where neutrophils are the predominant inflammatory cell type.

Acute Disease↗

PubMed2004

Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-kappaB and RhoA: implications for invasion and apoptosis.

The gastric pathogen Helicobacter pylori is associated with a progression to gastric cancer. The specific targets of H. pylori that might influence this progression are still unclear. Previous studies indicated that the gastric hormone gastrin, which may be increased in H. pylori infection, stimulates gastric expression of plasminogen activator inhibitor (PAI)-2, which is an inhibitor of the urokinase plasminogen activator and has previously been shown to be increased in gastric adenocarcinoma. Here, we report that H. pylori also increases PAI-2 expression. In gastric biopsies of H. pylori-positive subjects there was increased PAI-2, including subjects with plasma gastrin concentrations in the normal range. PAI-2 was expressed mainly in chief and mucous cells. In a gastric cancer cell line (AGS), H. pylori increased PAI-2 expression, which was associated with inhibition of H. pylori-stimulated cell invasion and apoptosis. The induction of PAI-2 by H. pylori was mediated by release of interleukin-8 and activation of cyclooxygenase-2, and interestingly, gastrin stimulated PAI-2 expression by similar paracrine pathways. The activation of NFkappaB was required for interleukin-8 and cyclooxygenase-2 activation but did not occur in cells responding to these paracrine mediators. The data suggest that induction of PAI-2 is a specific target in H. pylori infection, mediated at least partly by paracrine factors; induction of PAI-2 inhibits cell invasion and apoptosis and is a candidate for influencing the progression to gastric cancer.

Aged↗

PubMed2004

Identification and expression of a Burkholderia pseudomallei collagenase in Escherichia coli.

Extracellular protein profiles were compared for broth-grown cultures of Burkholderia pseudomallei and its avirulent close relative Burkholderia thailandensis. A number of protein bands were present in the B. pseudomallei profile but absent or less abundant in the B. thailandensis profile. Four such prominent secreted proteins were identified by using N-terminal sequencing coupled to searches of the B. pseudomallei genome sequence database. The genes for two proteins with similarity to carbohydrate-binding proteins, and a further protein homologous to known bacterial collagenases, were present in both B. pseudomallei and B. thailandensis. The putative collagenase gene was cloned and expressed as a fusion protein in Escherichia coli. Cell lysates from Escherichia coli containing the recombinant protein exhibited detectable gelatinase and collagenase activities.

Amino Acid Sequence↗

PubMed2004

Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer.

BACKGROUND & AIMS: Altered mucosal glycosylation in inflammatory bowel disease and colon cancer could affect mucosal bacterial adherence. This study aimed to quantify and characterize mucosa-associated and intramucosal bacteria, particularly Escherichia coli, in these conditions. METHODS: Mucosa-associated bacteria were isolated, after dithiothreitol mucolysis, from biopsy samples obtained at colonoscopy (Crohn's disease, n = 14 patients; ulcerative colitis, n = 21; noninflamed controls, n = 24) and at surgical resection (colon cancer, n = 21). Intramucosal bacteria were grown after gentamicin treatment followed by hypotonic lysis. RESULTS: Mucosa-associated and intramucosal bacteria were cultured more commonly in Crohn's disease (79%, P = 0.03; and 71%, P < 0.01, respectively), but not ulcerative colitis (38% and 48%), than in noninflamed controls (42% and 29%) and were commonly cultured from colon cancers (71% and 57%). Mucosa-associated E. coli, which accounted for 53% of isolates, were more common in Crohn's disease (6/14; 43%) than in noninflamed controls (4/24, 17%), as also were intramucosal E. coli: Crohn's disease, 29%; controls, 9%. E. coli expressed hemagglutinins in 39% of Crohn's cases and 38% of cancers but only 4% of controls, and this correlated (P = 0.01) with adherence to the I407 and HT29 cell lines. Invasion was cell-line dependent. E. coli, including nonadherent isolates, induced interleukin-8 release from the cell lines. E. coli adhesins showed no blood group specificity, excepting 1 cancer isolate (HM44) with specificity for the Thomsen-Friedenreich antigen, but they could be blocked by soluble plantain fiber. CONCLUSIONS: These studies support a central role for mucosally adherent bacteria in the pathogenesis of Crohn's disease and colon cancer. Soluble plant fibers that inhibit their adherence have therapeutic potential.

Bacterial Adhesion↗

PubMed2004

An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status.

BACKGROUND: Dietary selenium intakes in many countries, including the United Kingdom, are lower than international recommendations. No functional consequences of these lower intakes have been recognized, although experimental studies suggest that they might contribute to reduced immune function, increased cancer incidence, and increased susceptibility to viral disease. OBJECTIVE: The objective was to assess whether administration of small selenium supplements to otherwise healthy UK subjects leads to functional changes in immune status and the rates of clearance and mutation of a picornavirus: live attenuated polio vaccine. DESIGN: Twenty-two adult UK subjects with relatively low plasma selenium concentrations (<1.2 micromol/L, approximately 60% of those screened) received 50 or 100 microg Se (as sodium selenite) or placebo daily for 15 wk in a double-blind study. All subjects received an oral live attenuated poliomyelitis vaccine after 6 wk and enriched stable (74)Se intravenously 3 wk later. RESULTS: Selenium supplementation increased plasma selenium concentrations, the body exchangeable selenium pool (measured by using (74)Se), and lymphocyte phospholipid and cytosolic glutathione peroxidase activities. Selenium supplements augmented the cellular immune response through an increased production of interferon gamma and other cytokines, an earlier peak T cell proliferation, and an increase in T helper cells. Humoral immune responses were unaffected. Selenium-supplemented subjects also showed more rapid clearance of the poliovirus, and the poliovirus reverse transcriptase-polymerase chain reaction products recovered from the feces of the supplemented subjects contained a lower number of mutations. CONCLUSIONS: The data indicate that these subjects had a functional selenium deficit with suboptimal immune status and a deficit in viral handling. They also suggest that the additional 100 microg Se/d may be insufficient to support optimal function.

Adult↗

PubMed2004

Human norovirus infection and the lessons from animal caliciviruses.

PURPOSE OF REVIEW: Human noroviruses are a major cause of infectious intestinal disease, particularly in the health sector, with considerable knock-on effects on care provision through ward closures and staff sickness. This review will describe recent advances in our understanding of human noroviruses. In addition, we will consider related nonhuman caliciviruses to highlight some potential difficulties in the control of caliciviral disease. RECENT FINDINGS: Using more sensitive reverse transcriptase polymerase chain reaction based assays, noroviruses are now recognized as the most common cause of infectious intestinal disease in the community, as well as outbreaks of the infectious intestinal disease. After recovery from acute disease, some individuals continue shedding norovirus, particularly if immunosuppressed. The noroviruses are extremely variable, which has important implications for protection following challenge, and for future vaccination. From amongst this variability, new strains have emerged with the potential to spread widely. Recently a mouse norovirus has been identified which will afford new insights into the biology of these important viruses. Studies on human susceptibility have identified some resistant individuals in the population and a potential virus receptor, which may lead to the development of novel antiviral therapies. SUMMARY: Lack of cell culture systems for the human noroviruses is being overcome by molecular technologies. Such studies have provided new insight into the significance and epidemiology of these viruses and opened the possibility of disease control through vaccination. Work on nonhuman caliciviruses has interesting parallels with human noroviruses, and provides new insights into the understanding of these important human pathogens.

Animals↗

PubMed2004

Characterization of multidrug-resistant typhoid outbreaks in Kenya.

We characterized by antibiotic susceptibility, plasmid analysis, incompatibility grouping, and pulsed-field gel electrophoresis (PFGE) of XbaI- and SpeI-digested DNA 102 Salmonella enterica serovar Typhi (serovar Typhi) isolated from recent outbreaks of typhoid in three different parts of Kenya. Only 13.7% were fully susceptible, whereas another 82.4% were resistant to each of the five commonly available drugs: ampicillin, chloramphenicol, and tetracycline (MICs of >256 microg/ml); streptomycin (MIC, >1,024 microg/ml); and cotrimoxazole (MIC of >32 microg/ml). Resistance to these antibiotics was encoded on a 110-kb self-transferable plasmid of IncHI1 incompatibility group. The MICs of nalidixic acid (MIC, 8 to 16 micro g/ml) and ciprofloxacin (MIC of 0.25 to 0.38 micro g/ml) for 41.7% of the 102 serovar Typhi isolates were 5- and 10-fold higher, respectively, than for sensitive strains. Amplification by PCR and sequencing of the genes coding for gyrase (gyrA and gyrB) and topoisomerase IV (parE and parC) within the quinolone resistance-determining region revealed that the increase in the MICs of the quinolones had not resulted from any significant mutation. Analysis of genomic DNA from both antimicrobial agent-sensitive and multidrug-resistant serovar Typhi by PFGE identified two distinct subtypes that were in circulation in the three different parts of Kenya. As the prevalence of multidrug-resistant serovar Typhi increases, newer, more expensive, and less readily available antimicrobial agents will be required for the treatment of typhoid in Kenya.

Adult↗

PubMed2004

Phenotypic and genotypic changes in Salmonella enterica subsp. enterica serotype typhimurium during passage in intestines of broiler chickens fed on diets that included ionophore anticoccidial supplements.

The effect of continuous in-feed administration of anticoccidial agents on antimicrobial sensitivity and the level of bacterial shedding in poultry experimentally infected with Salmonella enterica subsp. enterica serotype Typhimurium definitive type 104 (DT104) were investigated. On day 0, 1,200 1-day-old Salmonella-free broiler chicks were placed into 50 pens, and the pens were randomly allocated to one of five treatments: nonsupplemented (negative control; T1), monensin at 120 mg/kg of diet (T2), salinomycin at 60 mg/kg of diet (T3), semduramicin at 20 mg/kg of diet (T4), or semduramicin at 25 mg/kg of diet (T5). Each bird was inoculated with a well-characterized strain of serotype Typhimurium DT104 on day 10. On day 49, the birds were euthanatized humanely. Bulk fecal samples were collected on days 13, 43, and 48 and were examined for organisms which had acquired resistance. The genetic basis of acquired resistance was determined from representative samples of isolates. Of 784 Salmonella-selective plates supplemented with antimicrobial agents, only 33 showed growth. These isolates came from all treatment regimens, including the nonsupplemented control. A number of phenotypic changes were observed; these included changes in motility, phage type, and agglutination properties. Supplementation of the diet with an anticoccidial drug does not appear to affect antimicrobial resistance or the level of excretion of salmonellae. Most of the changes observed do not seem to be related to the presence of a supplement in feed. Salmonellae appear to be capable of acquiring antimicrobial resistance and phenotypic changes independently of specific antimicrobial selection pressures.

Animal Feed↗

PubMed2004

Functional correlation of P-glycoprotein expression and genotype with expression of the human immunodeficiency virus type 1 coreceptor CXCR4.

The aim of this study was to investigate the relationship between lymphocyte P-glycoprotein (P-gp) expression and genotype in vivo and the expression of lymphocyte receptors critical in the life cycle of human immunodeficiency virus type 1 (HIV-1), i.e., CD4, CCR5, and CXCR4. Using flow cytometry to quantify each membrane receptor/transporter, we demonstrate a highly significant correlation between P-gp protein expression and the expression of CXCR4 (rho = 0.874; P < 0.0001). Furthermore, confocal microscopy showed colocalized expression of CXCR4 and P-gp in the lymphocyte membrane. This significant relationship was also apparent at the mRNA level by use of reverse transcription-PCR (rho = 0.61; P < 0.005) and was present in both phytohemagglutinin-stimulated and unstimulated peripheral blood mononuclear cells. Genotypic analysis of the C3435T single-nucleotide polymorphism of P-gp confirmed significantly higher levels of P-gp in C (range, 2.45 to 11.00 relative fluorescence units [RFU])- than in T (range, 0.25 to 5.00 RFU)-homozygous individuals (P = 0.0088; 95% confidence interval [95% CI], 0.7 to 6.3 RFU). An equivalent association between CXCR4 levels and C (range, 12.7 to 44.1 RFU) versus T (range, 3 to 18.9 RFU) genotype was also demonstrated (P = 0.0019; 95% CI, 5.4 to 23.7). Functionally, although these correlates had no impact on HIV-1 production from either X4- or R5-tropic virus, expression correlated significantly with the activity of the HIV-1 protease inhibitor (PI) saquinavir for both P-gp (rho = 0.75; P = 0.0019) and CXCR4 (rho = 0.71; P = 0.0041). This study defines an association between P-gp (expression and genotype) and CXCR4 that may have implications for the selection of viral tropism and the access of drugs to protease for specific tropic types. The interplay between these two proteins may also influence the viral genotypes which escape effective chemotherapy and which therefore have the opportunity to evolve resistance to PIs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Respiratory syncytial virus and metapneumovirus in children over two seasons with a high incidence of respiratory infections in Brazil.

Acute respiratory infections (ARI) are one of the most important causes of death in children. Human metapneumovirus (HMPV), a virus first described in 2001, has now been detected in almost all continents. HMPV causes bronchiolitis and pneumonia with a clinical spectrum similar to respiratory syncytial virus (RSV). We describe the incidence of HMPV and RSV during two consecutive seasons with a high incidence of ARI in Aracaju, Brazil. HMPV was responsible for 24% of cases of bronchiolitis in the 1st season (April-May 2002) but was not found in the 2nd year (April-May 2003). RSV was recovered from 61 (55%) children with ARI in 2002 and from 72 (68%) in 2003. Children with RSV bronchiolitis in 2002 had more hypoxia but less wheezing than in 2003. The incidence of HMPV and RSV genotypes causing bronchiolitis varied between the years. Long-term prospective studies are required to better describe the epidemiology of these viruses in children.

Brazil↗

PubMed2003

Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: role in epithelial cell migration.

Epithelial cell responses to bacterial infection include induction of matrix metalloproteinase 7 (MMP-7). Here, we identify increased MMP-7 expression in the gastric epithelium in response to the oncogenic bacterium Helicobacter pylori, and report on the mechanisms and consequences for gastric epithelial cell migration. In patients infected with H. pylori, there was increased MMP-7 in gastric biopsies detected by western blot. MMP-7 was localized to the advancing edge of migrating gastric epithelial cell colonies, including lamellipodia. Rates of spreading of gastric gland cells were higher in H. pylori-infected cultures compared with control, and this was inhibited by antisense oligonucleotides to MMP-7. Complementary data were obtained in a gastric cancer cell line (AGS cells). In the latter, H. pylori induced expression of an MMP-7-luciferase promoter/reporter vector through mechanisms that involved activation of Rho and Rac. RhoA acted through activation of both NF-kappaB and AP-1, whereas Rac activated NF-kappaB but not AP-1. MMP-7 is commonly upregulated in gastric cancer; since H. pylori is a recognized gastric carcinogen, the data suggest a new mechanism by which the bacterium might predispose towards gastric neoplasia.

Blotting, Western↗