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PubMed2001

SmaI macrorestriction analysis of Italian isolates of erythromycin-resistant Streptococcus pyogenes and correlations with macrolide-resistance phenotypes.

High rates of erythromycin resistance among Streptococcus pyogenes strains have been reported in Italy in the last few years. In this study, 370 erythromycin-resistant (MIC, > or = 1 microg/mL) Italian isolates of this species obtained in 1997-1998 from throat swabs from symptomatic patients were typed by analyzing SmaI macrorestriction fragment patterns by pulsed-field gel electrophoresis (PFGE). Among the typable isolates (n = 341; the genomic DNA of the remaining 29 isolates was not restricted by SmaI), 48 distinct PFGE types were recognized, of which 31 were recorded in only one isolate (one-strain types). Fifty-two percent of typable isolates fell into three type clusters and 75% into six, suggesting that erythromycin-resistant group A streptococci circulating in Italy are polyclonal, but the majority of them probably derives from the spread of a limited number of clones. In parallel experiments, the 370 test strains were characterized for the macrolide resistance phenotype: 80 were assigned to phenotype cMLS, 89 to phenotype iMLS-A, 33 to phenotype iMLS-B, 11 to phenotype iMLS-C, and 157 to phenotype M. There was a close correlation between these phenotypic data and the genotypic results of PFGE analysis, the vast majority of the isolates assigned to individual PFGE classes belonging usually to a single phenotype of macrolide resistance. All of the 29 untypable isolates belonged to the M phenotype. Further correlations were observed with tetracycline resistance.

Anti-Bacterial Agents↗
PubMed2002

Activity of ketolide ABT-773 (cethromycin) against erythromycin-resistant Streptococcus pneumoniae: correlation with extended MLSK phenotypes.

OBJECTIVES: (i) To determine the inhibitory and bactericidal activities of ABT-773, a novel ketolide, against sensitive and erythromycin-resistant pneumococci; (ii) to subdivide erythromycin-resistant pneumococci into resistance phenotypes, more extensive than the conventional M and MLS(B) groups, by assessing susceptibilities to, and interactions between, erythromycin (14-membered macrolide), clindamycin (lincosamide), rokitamycin (16-membered macrolide), ABT-773 (ketolide), quinupristin (streptogramin B) and dalfopristin (streptogramin A). METHODS: MICs and MBCs of ABT-773 were determined for 165 strains of pneumococci (113 resistant to erythromycin). Extended phenotypes for the erythromycin-resistant strains were described in terms of intrinsic susceptibility to, and induction of resistance by, the antibiotics listed above. RESULTS: Erythromycin-resistant strains could be divided into 10 extended phenotypes (designated II-XI), two of which (II and IX) predominated. ABT-773 at 0.12 mg/L inhibited 109 strains (median 0.03 mg/L). MICs for the other four strains (of phenotypes X and XI) were 0.25-1 mg/L. MICs were only slighter higher when measured on agar in CO(2) than by the NCCLS method (in broth in air). MBCs were usually < or = 2 x MIC, but for 10 strains (eight of phenotype X, one each of types IX and XI) MBCs were > 1 mg/L, and three of the latter (all type X) were tolerant. Clones of reduced susceptibility (MICs 1-8 mg/L, increased by up to 32-fold) could be isolated from some strains of phenotypes VII, IX and X, but not from those of type II (efflux mechanism) or from erythromycin-sensitive strains. CONCLUSIONS: ABT-773 was active against all 113 erythromycin-resistant pneumococci tested, which belonged to 10 phenotypes. Extended phenotyping of pneumococci revealed interesting and potentially useful subdivisions of the classical phenotypes.

Drug Resistance, Bacterial↗
PubMed2004

Novel recombinant phenotypic assay for clonal analysis of reverse transcriptase mutations conferring drug resistance to HIV-1 variants.

OBJECTIVE: A novel rapid reverse transcriptase (RT) recombinant HIV-1 drug-susceptibility assay was developed to evaluate resistance to RT inhibitors. MATERIAL AND METHODS: HIV-1 RTs from five treatment-naive and 10 highly active antiretroviral therapy-experienced patients were evaluated. HIV-1 isolates recovered by culturing peripheral blood mononuclear cells from patients were used in the conventional isolate phenotype analysis. Recombinant HIV-1 strains were obtained by cloning the RT gene amplified from the supernatant of HIV-1 cultures in a plasmid carrying the HIV-1 strain HXB2 backbone, and the most represented clone for each virus isolate was then tested for antiviral drug susceptibility in parallel with HIV-1 isolates. RESULTS: Comparison of conventional virus isolate and the novel recombinant virus phenotypic assays showed a large concordance of results. However, some discrepant results were observed, in that higher drug-resistance levels were detected by the conventional isolate phenotypic assay in HIV-1 isolates showing the presence of a mixture of HIV-1 variants, whereas the novel recombinant phenotypic assay could more precisely detect the level of drug resistance of the single viral clones selected for the analysis. DISCUSSION: The novel recombinant phenotype assay, compared with the conventional virus isolate phenotype assay, showed widely overlapping results. The comparison of the two assays show that the conventional phenotypic assay is able to identify more efficiently the combined effect of drug-resistant viral variants, whereas the novel recombinant phenotypic assay is better able to define the level of drug resistance of the single viral variants. In addition, rapidity (2 weeks versus 4 weeks required by the reference recombinant assay and 6 weeks required by the conventional virus isolate phenotypic assay) is a major advantage of the novel assay.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls.

Interindividual differences in metabolism of the soy isoflavone, daidzein, to equol and O-desmethylangolensin (ODMA) by human gut bacteria, have been associated with altered risk of cancer and other chronic diseases, according to some studies. Differences have been reported in the prevalence of the equol-producer phenotype among populations, with a higher prevalence in soy-consuming Asian populations than in Western populations. To date, prevalence of the daidzein-metabolizing phenotypes in Asians, compared with Caucasians, has not been evaluated in the context of a standardized phenotyping method. We assessed the prevalence of equol- and ODMA-producer phenotypes in 91 Korean American (KA) women and girls living in the Seattle, Washington area and compared this with previous similarly collected prevalence data in Caucasian American (CA) women and girls (n = 222). We also compared the dietary habits of the 2 groups. Isoflavonoid concentrations in first-void morning urines, collected after a 3-d soy challenge, were used to establish equol-, and ODMA-producer phenotypes (>44 microg/L). The prevalence of the equol-producer phenotype was higher (51 vs. 36%; P = 0.015) and the ODMA-producer phenotype was lower (84 vs. 92%, P = 0.03) in KA than in CA women and girls. KAs consumed approximately 3 times more soy foods than the CAs, but no significant associations were found between the consumption of soy foods and equol-producer phenotype. Our findings support the reports that, compared with Western populations, Asian populations have a higher equol-producer prevalence. The additional observation that the prevalence of the ODMA-producer phenotype is lower in KAs suggests that daidzein-metabolizing patterns in general may differ between KAs and CAs.

Adult↗
PubMed1992

Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites.

The wide variations in urinary bladder and colo-rectal cancer incidence in humans have been attributed in part to metabolic factors associated with exposure to carcinogenic aromatic and heterocyclic amines. Cytochrome P-4501A2 (CYP1A2), which catalyses N-oxidation, and acetyltransferase (NAT2) which catalyses N- and O-acetylation, both appear to be polymorphically distributed in human populations; and slow and rapid NAT2 phenotypes have been implicated as risk factors for these cancers. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. For the NAT2 phenotype, we confirm the valid use of the urinary molar ratio of AFMU/1-methylxanthine, even in alkaline urines. For the CYP1A2 phenotype, the urinary molar ratio of [1,7-dimethylxanthine + 1,7-dimethyluric acid]/caffeine, taken at 4-5 h after caffeine ingestion, was identified from pharmacokinetic analyses of 12 subjects as being better correlated (r = 0.73; p = 0.007) with the rate constant for caffeine 3-demethylation than other previously suggested ratios. This procedure was then used to determine the CYP1A2 phenotype in subjects from Arkansas (n = 101), Italy (n = 95), and China (n = 78). Statistical and probit analyses of nonsmokers indicated that the CYP1A2 activity was not normally distributed and appeared trimodal. This trimodality allowed arbitrary designation of slow, intermediate, and rapid phenotypes, which ranged from 12-13% slow, 51-67% intermediate, and 20-37% rapid, in the different populations. A reproducibility study of 13 subjects over a 5 day or 5 week period showed that, with one exception, intraindividual variability did not alter this CYP1A2 phenotypic classification. Induction of CYP1A2 by cigarette smoking was also confirmed by the increased caffeine metabolite ratios observed in the Arkansas and Italian smokers (blonde tobacco). However, Italian smokers of black tobacco and Chinese smokers did not appear to be induced. Furthermore, probit analyses of Arkansas and Italian blonde tobacco smokers could not discriminate between phenotypes, apparently as a consequence of enzyme induction.

Adult↗
PubMed1995

A multifamily study on the relationship between CYP2C19 genotype and s-mephenytoin oxidation phenotype.

It has recently been shown that the most common mutation (named m1) in both Caucasian and Japanese poor metabolizers (PM) of S-mephenytoin is a single base pair mutation (G-->A) in exon 5 of the CYP2C19 gene. In Japanese, a second defective allele of CYP2C19 named m2 consists of a G-->A mutation in exon 4. In the present study, we have investigated the inheritance of the CYP2C19 wild type allele (wt) and the two defective alleles (m1 and m2) in families of 11 Danish PM probands. The study was carried out for two principal reasons. First, we wanted to confirm the autosomal recessive inheritance of the defective alleles, and second, we wanted to examine the specificity and sensitivity of the CYP2C19 genotyping test. Individuals were phenotyped by measuring the ratio of S/R mephenytoin excreted in the urine after administration of mephenytoin, and genotyping was carried out by a PCR-based DNA amplification procedure. The genotypes of nine of the 11 probands were consistent with their phenotypes. Eight were homozygous m1/m1, and one was heterozygous m1/m2. The genotypes of two putative PM probands (wt/m1) were not consistent with their phenotypes. On the basis of extended phenotyping (additional late urine collections (24-36 h) and acidification of urine), one of these could probably be reclassified as an extensive metabolizer (EM) while the other was considered to be a true PM. This suggests the presence of an additional unknown mutant allele in the latter. Seven of the 41 phenotyped relatives in the 11 families were phenotyped as PMs, and with the exception of the father of family 10, their genotypes (m1/m1) were consistent with their phenotypes. Extended phenotyping (acidification of urine) suggested that the father of family 10 in fact is an EM and hence that his genotype (wt/m1) is concordant with his phenotype. Thus, the specificity of genotyping tests for PM was 100%, while the sensitivity was 15/16 or 94%. Our study provides unequivocal evidence for autosomal recessive inheritance of the PM trait.

Adult↗
PubMed2004

Phenotypic susceptibility to nonnucleoside inhibitors of virion-associated reverse transcriptase from different HIV types and groups.

OBJECTIVES: To evaluate a phenotype assay based on plasma reverse transcriptase (RT) to assess HIV susceptibility to nonnucleoside RT inhibitors (NNRTIs). To compare RT-based phenotype with recombinant virus assay (RVA) phenotype- and genotype-based analysis. To assess group O and HIV-2 susceptibility to NNRTIs in correlation with genotype polymorphisms. METHODS: RT activity was quantified and its susceptibility to efavirenz, nevirapine, and delavirdine measured as drug concentration resulting in 50% inhibition. RT phenotype was compared with genotype analysis. Eighteen plasma samples from 14 group M- and culture supernatants from 4 group M-, 9 group O-, and 7 HIV-2-infected patients were investigated. RT-based and RVA-based phenotypes were compared for identical plasma from 9 group M-infected patients. RESULTS: RT-based and RVA-based phenotypes were in complete agreement. RT-based phenotype- and genotype-predicted susceptibility were concordant for all but 1 group M samples. One plasma showed susceptibility to 3 NNRTIs by phenotypes, despite the presence of 101E and 106I/V residues. The HIV-2 RTs were totally resistant to the NNRTIs tested. Among HIV-1 group O, 6 were totally resistant to NNRTIs independently of the presence of the 181C mutation and 3 were susceptible to some NNRTIs. CONCLUSION: Plasma RT-based phenotype could be useful as a simple alternative for monitoring resistance to NNRTIs. This assay is suitable for highly divergent strains. It would be particularly useful for large epidemiologic survey of the natural HIV polymorphism and the potential impact in emergence of drug resistance, particularly to nevirapine, widely used to prevent mother-to-child transmission.

Anti-HIV Agents↗
PubMed2007

Asthma phenotypes.

PURPOSE OF REVIEW: Asthma is a heterogeneous disorder presenting with many phenotypes. Precise phenotypic definition has eluded the medical research community for years, despite recognition of different disease subtypes. Improved phenotypic characterization and knowledge of underlying pathobiology is necessary for linkage of specific genotypes with clinical disease manifestations. RECENT FINDINGS: Phenotyping has been difficult because asthma is likely to be comprised of overlapping syndromes with varying origins and heterogeneous pathobiology. Currently, the field is too reliant on classification by trigger or symptoms. Since genotypic and phenotypic heterogeneity are inherent in asthma, patients presenting with different asthma phenotypes may need tailored therapies. Studies have begun to link genetics with disease mechanism and therapeutic response. As disease etiology, onset, progression and severity vary greatly among patients, however, the relative contribution of genetic factors may be difficult to ascertain. Definition of the full array of complex biological consequences of molecular target modulation is a prerequisite for therapies based on this concept. SUMMARY: The advent of targeted therapies for asthma and clinical trials based on phenotype and genotype have raised interest in more accurate description of asthma phenotypes. Therapies based on phenotypic and genotypic characteristics may be useful in asthma management. A variety of factors, however, must be addressed before such approaches become standard.

Aspirin↗
PubMed1985

Correlation of cell-envelope phenotypes of Neisseria gonorrhoeae with site of infection and serogroup.

The envelope phenotypes and coagglutination (CoA) W serogroups of 301 unselected clinical isolates of Neisseria gonorrhoeae were studied. Of the 287 isolates from infections acquired in the Edinburgh area, 252 (88%) were of the wild-type phenotype, 17 (6%) were of Env phenotype with increased permeability of the cell envelope, and 18 (6%) were of Mtr phenotype with reduced permeability of the cell envelope. Mtr strains were isolated significantly more often from homosexual men than from heterosexual men and women (p less than 0.001). Of the isolates from homosexual men there were considerably fewer Mtr phenotypes among rectal isolates than among urethral and throat isolates. All isolates from homosexual men, 57% from heterosexual men and 52% from women were of CoA serogroup WII (including WII/WIII). Although the Mtr phenotype was strongly associated with serogroup-WII isolates from homosexual men, there was no such correlation between the Mtr phenotype and serogroup-WII isolates from heterosexual patients. It is suggested that hydrophobic compounds in the rectal environment are not the major factor in selecting serogroup-WII strains of Mtr phenotype associated with homosexually acquired infection. The hypothesis that the Mtr phenotype and serogroup WII are selected independently as a result of a more general selective pressure such as antibiotic usage, common to all infected sites, is discussed.

Agglutination Tests↗
PubMed2004

A cross-genomic approach for systematic mapping of phenotypic traits to genes.

We present a computational method for de novo identification of gene function using only cross-organismal distribution of phenotypic traits. Our approach assumes that proteins necessary for a set of phenotypic traits are preferentially conserved among organisms that share those traits. This method combines organism-to-phenotype associations,along with phylogenetic profiles,to identify proteins that have high propensities for the query phenotype; it does not require the use of any functional annotations for any proteins. We first present the statistical foundations of this approach and then apply it to a range of phenotypes to assess how its performance depends on the frequency and specificity of the phenotype. Our analysis shows that statistically significant associations are possible as long as the phenotype is neither extremely rare nor extremely common; results on the flagella,pili, thermophily,and respiratory tract tropism phenotypes suggest that reliable associations can be inferred when the phenotype does not arise from many alternate mechanisms.

Bacterial Proteins↗
PubMed2006

Erythrocyte Lewis (A+B-) host phenotype is a factor with familial clustering for increased risk of Helicobacter pylori-related non-cardiac gastric cancer.

BACKGROUND: The purpose of the present study was to test whether host erythrocyte Lewis phenotypes correlated with the risk of gastric cancers. Because of the association of gastric cancer with familial clustering, cancer relatives were investigated as to whether they had unique distribution of Lewis phenotypes. METHODS: The study prospectively enrolled 74 Helicobacter pylori-positive gastric cancer patients and 100 H. pylori-positive duodenal ulcer patients to serve as non-cancer controls after panendoscopy. In addition, 433 family members from the 74 index cancer and 100 non-cancer control patients were enrolled. All enrolled cases were checked for their H. pylori status and erythrocyte Lewis phenotypes, defined as Le(a-b-), Le(a-b+), Le(a+b-), and Le(a+b+) subtypes by the anti-Le(a) and anti-Le(b) monoclonal antibodies. RESULTS: These H. pylori-infected patients with gastric cancer had a higher rate of Le(a+b-) phenotype and a lower rate of Le(a-b+) phenotype than the non-cancer duodenal ulcer controls (20.3% vs 9%; 51.4% vs 72%, P < 0.05). Among these H. pylori-infected patients, the risk of the patients with Le(a+b-) phenotype having gastric cancer was 3.15-fold higher as compared with those with the Le(a-b+) phenotype (P = 0.02, 95% confidence interval: 1.26-7.87). The offspring and cousins of the cancer patients had a higher rate of Le(a+b-) phenotype as compared to either that of the spouses of cancer index patients or to that of the family members of the non-cancer control (P < 0.05). CONCLUSION: Le(a+b-) phenotype of the H. pylori-infected host could be a risk factor (with familial clustering) for gastric carcinogenesis.

Aged↗
PubMed2004

Immunohistochemically detectable Cdx2 is present in intestinal phenotypic elements in early gastric cancers of both differentiated and undifferentiated types, with no correlation to non-neoplastic surrounding mucosa.

It has previously been reported that Cdx2 is the useful prognostic and intestinal phenotypic marker in advanced gastric cancers (GC). In this study, Cdx2 expression and phenotype in early GC and non-neoplastic surrounding mucosa were examined. A total of 130 early GC (70 intramucosal and 60 submucosally invasive cancers) histologically and phenotypically were evaluated. The expression of Cdx2 was assessed by immunohistochemistry. The lesions were phenotypically divided into 44 gastric (G), 42 gastric and intestinal mixed (GI), 30 intestinal (I), and 14 null (N) types, independent of the histological classification. Most of the early GC were Cdx2-positive, nuclear staining being strongly associated with intestinal phenotypic expression. Early differentiated cancers tended to feature both Cdx2 and intestinal phenotypic expression, while their undifferentiated counterparts were more likely to demonstrate only gastric phenotypic expression (P < 0.05). The phenotypes of six intramucosal microcarcinomas did not correlate with those of adjacent normal glands. These data suggest that Cdx2 is expressed in the very early stage of gastric carcinogenesis in association with the shift from gastric to intestinal phenotypic expression. This appears to occur in differentiated cancers at an earlier stage than in undifferentiated ones, and may be linked to suppression of expansion of malignant cells.

Adenocarcinoma↗
PubMed2004

Clinical phenotypes of COPD: results of a Japanese epidemiological survey.

OBJECTIVE: The Global Initiative for Obstructive Lung Disease characterizes COPD as airflow limitation caused by parenchymal destruction and/or small airway disease. This report characterizes the clinical features of these two phenotypes of COPD in Japan. METHODOLOGY: COPD was diagnosed by spirometric airflow limitation (FEV(1)/FVC < 70%), and all subjects underwent chest CT scanning. Patients with diffuse low attenuation areas (LAA) on CT scan were categorized as the emphysema-dominant phenotype; those with little LAA were categorized as the airway disease-dominant phenotype. The two groups were compared to identify significant clinical or demographic differences. RESULTS: Of the 1438 patients analysed, 1294 (90%) were classified as having an emphysema-dominant phenotype and 144 (10%) as having an airway disease-dominant phenotype. The airway disease-dominant phenotype was: more common than the emphysema-dominant phenotype in women (15%vs. 7%, P < 0.01) and in non-smokers (6%vs. 2%, P < 0.05); was more commonly complicated by asthmatic features (35%vs. 21%, P < 0.01); and had higher IgE and eosinophil levels (P < 0.05) and less lung function impairment. CONCLUSION: This analysis is the first to clinically define two phenotypes of COPD in a Japanese epidemiological survey. There appear to be striking differences as well as overlap between these two groups. Further research is warranted to determine the significance of COPD phenotypes.

Female↗
PubMed2005

Modifier genes play a significant role in the phenotypic expression of PKD1.

BACKGROUND: Polycystic kidney disease type 1 (PKD1) is characterized by extreme variation in the severity and progression of renal and extrarenal phenotypes. There are significant familial phenotype differences; but it is not clear if this is due to differences in PKD1 mutations, differences in genetic background, or both. METHODS: A total of 315 affected relatives (83 PKD1 families) without end-stage renal disease (ESRD) were evaluated for disease markers, including renal volume, creatinine clearance, proteinuria, liver cysts, and hypertension. Of these patients, 19% progressed to ESRD within 1 to 10 years after the initial examination. Nested analysis of variance was used to investigate interfamilial and intrafamilial differences in these phenotypes. Heritability analyses were used to estimate the effect of the genetic background on phenotypic variability. The age of onset of ESRD was also analyzed with an additional 389 family members from the same PKD1 families without clinical evaluation but with data on age of onset of ESRD (or age without ESRD). RESULTS: There were significant phenotype differences between patients with the same mutation and different genetic backgrounds. The phenotypic variation between patients with different mutations and different genetic backgrounds was not significantly greater than the variation between patients with the same mutation and different genetic backgrounds. However, when the 389 family members were included, both the mutation and modifier genes had significant effects on the age of onset of ESRD. Inherited differences in genetic background were estimated to account for 18% to 59% of the phenotypic variability in PKD1 disease markers in patients prior to ESRD and in the subsequent progression to ESRD (43% heritability) in the 315 patients who were clinically evaluated. CONCLUSION: Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.

Adult↗
PubMed2006

Fetal alcohol spectrum disorders in children residing in Russian orphanages: a phenotypic survey.

BACKGROUND: Alcohol use in Russia is among the highest in the world. Over 600,000 children reside in institutional care in Russia, most of them in baby homes and orphanages. The actual prevalence of fetal alcohol spectrum disorders (FASD) among these children is unknown. Therefore, we performed a systematic survey of phenotypic features associated with prenatal alcohol exposure among institutionalized Russian children and related these findings to their growth, development, medical, and social histories. METHODS: Phenotypic screening was conducted of all 234 baby home residents in the Murmansk region of Russia (mean age 21+12.6 months). Phenotypic expression scores were devised based on facial dysmorphology and other readily observable physical findings. Growth measurements from birth, time of placement in the baby home, and at present were analyzed. In addition, the charts of 64% of the children were randomly selected for retrospective review. Information collected included maternal, medical, developmental, and social histories. RESULTS: Thirteen percent of children had facial phenotype scores highly compatible with prenatal alcohol exposure and 45% had intermediate facial phenotype scores. These scores correlated with maternal gravidity and age. At least 40% of mothers in whom history was available ingested alcohol during pregnancy; some also used illicit drugs and tobacco. Z scores for growth measurements corresponded to phenotypic score, as did the degree of developmental delay. Children with no or mild delay had significantly lower phenotypic scores than those with moderate or severe delay (p = 0.04); more than 70% of children with high phenotypic scores were moderately or severely delayed. CONCLUSIONS: More than half of residents of the baby homes in Murmansk, Russia, have intermediate (45%) or high (13%) phenotypic expression scores suggesting prenatal exposure to alcohol. Despite good physical care, stable daily routine, availability of well-trained specialists, and access to medical care, these vulnerable children show significant growth and developmental delays compared with their institutionalized peers.

Anthropometry↗
PubMed1992

Adhesion of Salmonella typhimurium to porcine intestinal epithelial surfaces: identification and characterization of two phenotypes.

Salmonella typhimurium 798 is known to persistently colonize swine. A key step required to initiate colonization of intestines is adhesion of the organism to the intestinal epithelium. However, S. typhimurium 798 initially failed to attach to porcine enterocytes in vitro. An enrichment procedure was used to select adhesive S. typhimurium, and when cells of one colony type were grown in tryptone phosphate broth they were adhesive. Cells from a colony with a different morphology were not adhesive. Adhesion was time dependent, with maximal adhesion occurring at 1 h. As determined by electron microscopy, cells of the adhesive phenotype had pili while none of the cells with the nonadhesive phenotype produced pili. The pili on the adhesive cells were morphologically similar to type 1 pili. Mannose (0.5%) did not affect adhesion, suggesting that the adhesin on strain 798 did not recognize mannose as a receptor. An analysis of envelope proteins from cells of both phenotypes showed that the adhesive-phenotype cells expressed at least 10 unique proteins ranging in size from 20 to 60 kDa. Absorbed antiserum against cells of the adhesive phenotype agglutinated adhesive cells and was used to detect unique surface antigens on the cells of the adhesive phenotype by Western blots (immunoblots). These antigens were in the range of 30 kDa in size. An envelope extract competitively inhibited the binding of S. typhimurium to enterocytes, as did Fab fragments prepared from the absorbed serum. Cells of both phenotypes contained two plasmids, and each had identical restriction digestion patterns. Cells of the adhesive phenotype consistently were found to be more readily phagocytosed by pig leukocytes, and once in the phagocytes they survived better than cells of the nonadhesive phenotype.

Animals↗
PubMed2006

Determining human immunodeficiency virus coreceptor use in a clinical setting: degree of correlation between two phenotypic assays and a bioinformatic model.

Two recombinant phenotypic assays for human immunodeficiency virus (HIV) coreceptor usage and an HIV envelope genotypic predictor were employed on a set of clinically derived HIV type 1 (HIV-1) samples in order to evaluate the concordance between measures. Previously genotyped HIV-1 samples derived from antiretroviral-naïve individuals were tested for coreceptor usage using two independent phenotyping methods. Phenotypes were determined by validated recombinant assays that incorporate either an approximately 2,500-bp ("Trofile" assay) or an approximately 900-bp (TRT assay) fragment of the HIV envelope gp120. Population-based HIV envelope V3 loop sequences ( approximately 105 bp) were derived by automated sequence analysis. Genotypic coreceptor predictions were performed using a support vector machine model trained on a separate genotype-Trofile phenotype data set. HIV coreceptor usage was obtained from both phenotypic assays for 74 samples, with an overall 85.1% concordance. There was no evidence of a difference in sensitivity between the two phenotypic assays. A bioinformatic algorithm based on a support vector machine using HIV V3 genotype data was able to achieve 86.5% and 79.7% concordance with the Trofile and TRT assays, respectively, approaching the degree of agreement between the two phenotype assays. In most cases, the phenotype assays and the bioinformatic approach gave similar results. However, in cases where there were differences in the tropism results, it was not clear which of the assays was "correct." X4 (CXCR4-using) minority species in clinically derived samples likely complicate the interpretation of both phenotypic and genotypic assessments of HIV tropism.

Computational Biology↗
PubMed1987

Expression of adenovirus E1B mutant phenotypes is dependent on the host cell and on synthesis of E1A proteins.

Adenovirus mutants containing genetic alterations in the gene encoding the E1B 19,000-molecular-weight (19K) tumor antigen induce the degradation of host cell chromosomal DNA (deg phenotype) and enhanced cytopathic effect (cyt phenotype) after infection of HeLa and KB cells. The deg and cyt phenotypes are a consequence of viral early gene expression in the absence of the E1B 19K protein. The role of the E1A proteins in induction of the cyt and deg phenotypes was investigated by constructing E1A-E1B double mutant viruses. Viruses were constructed to express the individual E1A 13S, 12S, or 9S cDNA genes in the presence of a mutation in the gene encoding the E1B 19K tumor antigen. Expression of either the 13S or 12S E1A proteins in the absence of functional E1B 19K protein produced the deg and cyt phenotypes. In contrast, a virus which expressed exclusively the 9S E1A gene product in the absence of the E1B 19K gene product did not induce the deg and cyt phenotypes, even at high multiplicities of infection. Therefore, both the 13S and 12S E1A gene products could directly or indirectly cause the deg and cyt phenotypes during infection of HeLa cells with an E1B 19K gene mutant virus. Furthermore, the deg phenotype was found to be host cell type specific, occurring in HeLa and KB cells but not in growth-arrested human WI38 cells. These results indicate that expression of the E1A trans-activating and transforming proteins is necessary for the induction of the cyt and deg phenotypes and that host cell factors also play a role.

Adenovirus Early Proteins↗