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2.
FEMS Microbiol Lett ; 196(2): 189-93, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11267778

ABSTRACT

A gene encoding a putative 2[4Fe--4S] ferredoxin (FdxA) was identified upstream of, and divergent to the peroxide stress defense gene ahpC of the microaerophilic pathogen Campylobacter jejuni. The transcription start site of fdxA was located 27 and 28 bp upstream of the fdxA start codon. Transcriptional fusions of the fdxA promoter to a lacZ reporter gene demonstrated that expression of fdxA is iron-induced, and thus oppositely regulated to the iron-repressed ahpC gene. Insertional mutagenesis of the fdxA gene did not affect microaerobic growth of C. jejuni, but significantly reduced aerotolerance of C. jejuni. The fdxA gene is the first reported iron-induced gene of C. jejuni, and encodes a novel component of its oxidative stress defense.


Subject(s)
Campylobacter jejuni/genetics , Ferredoxins/genetics , Iron/physiology , Aerobiosis , Amino Acid Sequence , Bacterial Proteins/genetics , Base Sequence , Campylobacter jejuni/growth & development , Campylobacter jejuni/metabolism , Gene Expression Regulation, Bacterial/drug effects , Genes, Reporter , Molecular Sequence Data , Mutagenesis, Insertional , Oxidative Stress , Oxidoreductases , Peptides/genetics , Recombinant Fusion Proteins , Sequence Homology, Amino Acid , Transcription, Genetic
3.
FEMS Microbiol Lett ; 188(2): 115-8, 2000 Jul 15.
Article in English | MEDLINE | ID: mdl-10913692

ABSTRACT

A lacZ-based reporter gene system was used to identify the promoter of the Campylobacter jejuni iron-responsive gene regulator Fur. In other Gram-negative bacteria, the fur promoter is usually located directly upstream of the fur gene and is often autoregulated in response to iron. In this study we demonstrate that expression of the C. jejuni fur gene is controlled from two promoters located in front of the first and second open reading frames upstream of fur. Neither of these promoters was iron-regulated, and the presence of both promoters in front of fur gives higher expression of the lacZ reporter than with either promoter alone. Expression from two distal promoters might be a mechanism for regulating the level of the C. jejuni Fur protein in response to unknown stimuli.


Subject(s)
Bacterial Proteins/genetics , Campylobacter jejuni/genetics , Metalloproteins/genetics , Promoter Regions, Genetic , Repressor Proteins/genetics , Campylobacter jejuni/metabolism , Iron/metabolism , Lac Operon , Open Reading Frames
4.
Nature ; 403(6770): 665-8, 2000 Feb 10.
Article in English | MEDLINE | ID: mdl-10688204

ABSTRACT

Campylobacter jejuni, from the delta-epsilon group of proteobacteria, is a microaerophilic, Gram-negative, flagellate, spiral bacterium-properties it shares with the related gastric pathogen Helicobacter pylori. It is the leading cause of bacterial food-borne diarrhoeal disease throughout the world. In addition, infection with C. jejuni is the most frequent antecedent to a form of neuromuscular paralysis known as Guillain-Barré syndrome. Here we report the genome sequence of C. jejuni NCTC11168. C. jejuni has a circular chromosome of 1,641,481 base pairs (30.6% G+C) which is predicted to encode 1,654 proteins and 54 stable RNA species. The genome is unusual in that there are virtually no insertion sequences or phage-associated sequences and very few repeat sequences. One of the most striking findings in the genome was the presence of hypervariable sequences. These short homopolymeric runs of nucleotides were commonly found in genes encoding the biosynthesis or modification of surface structures, or in closely linked genes of unknown function. The apparently high rate of variation of these homopolymeric tracts may be important in the survival strategy of C. jejuni.


Subject(s)
Bacterial Proteins , Campylobacter jejuni/genetics , Genetic Variation , Genome, Bacterial , Amino Acid Sequence , Bacterial Toxins/genetics , Campylobacter jejuni/classification , Campylobacter jejuni/metabolism , Chemotaxis , Food Contamination , Humans , Lipopolysaccharides/biosynthesis , Membrane Proteins/metabolism , Methyl-Accepting Chemotaxis Proteins , Molecular Sequence Data , Phylogeny
5.
FEMS Microbiol Lett ; 179(2): 209-15, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10518717

ABSTRACT

The mechanisms whereby Campylobacter jejuni translocates across the host intestinal epithelium are not yet understood and the transepithelial route remains undefined. During C. jejuni translocation, the transmonolayer electrical resistance (TER) across polarised monolayers of Caco-2 cells is not affected and the penetration of [(14)C]inulin across the monolayers does not increase. Over 24 h, however, bacteria damage the monolayer integrity, causing a decrease in the TER. These results support C. jejuni translocation through the cytoplasm of invaded cells (transcellular) rather than via intercellular spaces (paracellular).


Subject(s)
Bacterial Translocation , Campylobacter jejuni/physiology , Caco-2 Cells , Electric Impedance , Humans , Tight Junctions/microbiology
6.
Microbiology (Reading) ; 145 ( Pt 9): 2463-2475, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10517599

ABSTRACT

To survive and multiply in different environments, Vibrio cholerae has to coordinately regulate the expression of genes involved in adaptive responses. In many pathogens, adaptive responses, including pathogenic responses, are regulated by two-component regulator (TCR) systems. It is likely that members of a TCR family play a role in the regulation of processes involved in intestinal colonization, and therefore pathogenesis, in V. cholerae. We have identified and characterized a TCR system of V. cholerae: this system is a homologue of Escherichia coli PhoBR. The presence of a putative Pho box suggests that the V. cholerae phoBR operon is regulated by inorganic phosphate levels. The phoR and phoB genes are organized the same way as in E. coli. Mutation of the V. cholerae phoB gene affected the expression of the putative Pho regulon, including PhoA, but did not affect the production of cholera toxin. V. cholerae phoB mutants are less able to colonize rabbit intestine than wild-type V. cholerae. The addition of inorganic phosphate at a high concentration to the inoculum only partially restored the ability of the mutants to colonize the intestine, suggesting that the V. cholerae Pho regulon in vivo may not be regulated by inorganic phosphate levels alone.


Subject(s)
Bacterial Proteins/genetics , Gene Expression Regulation, Bacterial , Intestinal Mucosa/microbiology , Vibrio cholerae/genetics , Alkaline Phosphatase/metabolism , Anastomosis, Surgical , Animals , Bacterial Proteins/metabolism , Base Sequence , Cholera Toxin/metabolism , Cloning, Molecular , Conjugation, Genetic , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genes, Bacterial , Ileum/microbiology , Ileum/surgery , Molecular Sequence Data , Phosphates/metabolism , Protein Kinases/genetics , Protein Kinases/metabolism , Rabbits , Sequence Analysis, DNA , Vibrio cholerae/metabolism , Vibrio cholerae/pathogenicity
7.
J Bacteriol ; 181(20): 6371-6, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10515927

ABSTRACT

Expression of the peroxide stress genes alkyl hydroperoxide reductase (ahpC) and catalase (katA) of the microaerophile Campylobacter jejuni is repressed by iron. Whereas iron repression in gram-negative bacteria is usually carried out by the Fur protein, previous work showed that this is not the case in C. jejuni, as these genes are still iron repressed in a C. jejuni fur mutant. An open reading frame encoding a Fur homolog (designated PerR for "peroxide stress regulator") was identified in the genome sequence of C. jejuni. The perR gene was disrupted by a kanamycin resistance cassette in C. jejuni wild-type and fur mutant strains. Subsequent characterization of the C. jejuni perR mutants showed derepressed expression of both AhpC and KatA at a much higher level than that obtained by iron limitation, suggesting that expression of these genes is controlled by other regulatory factors in addition to the iron level. Other iron-regulated proteins were not affected by the perR mutation. The fur perR double mutant showed derepressed expression of known iron-repressed genes. Further phenotypic analysis of the perR mutant, fur mutant, and the fur perR double mutant showed that the perR mutation made C. jejuni hyperresistant to peroxide stress caused by hydrogen peroxide and cumene hydroperoxide, a finding consistent with the high levels of KatA and AhpC expression, and showed that these enzymes were functional. Quantitative analysis of KatA expression showed that both the perR mutation and the fur mutation had profound effects on catalase activity, suggesting additional non-iron-dependent regulation of KatA and, by inference, AhpC. The PerR protein is a functional but nonhomologous substitution for the OxyR protein, which regulates peroxide stress genes in other gram-negative bacteria. Regulation of peroxide stress genes by a Fur homolog has recently been described for the gram-positive bacterium Bacillus subtilis. C. jejuni is the first gram-negative bacterium where non-OxyR regulation of peroxide stress genes has been described and characterized.


Subject(s)
Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Campylobacter jejuni/genetics , Iron/metabolism , Oxidative Stress/genetics , Peroxidases , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors , Amino Acid Sequence , Catalase/genetics , Models, Genetic , Molecular Sequence Data , Oxidoreductases/genetics , Peroxides/pharmacology , Peroxiredoxins , Sequence Homology, Amino Acid
8.
J Bacteriol ; 181(16): 4798-804, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10438747

ABSTRACT

Microaerophiles like Campylobacter jejuni must resist oxidative stresses during transmission or infection. Growth of C. jejuni 81116 under iron limitation greatly increased the expression of two polypeptides of 26 and 55 kDa. The identification of these proteins by N-terminal amino acid sequencing showed both to be involved in the defense against oxidative stress. The 55-kDa polypeptide was identical to C. jejuni catalase (KatA), whereas the N terminus of the 26-kDa polypeptide was homologous to a 26-kDa Helicobacter pylori protein. The gene encoding the C. jejuni 26-kDa protein was cloned, and the encoded protein showed significant homology to the small subunit of alkyl hydroperoxide reductase (AhpC). The upstream region of ahpC encoded a divergent ferredoxin (fdxA) homolog, whereas downstream sequences contained flhB and motB homologs, which are involved in flagellar motility. There was no evidence for an adjacent homolog of ahpF, encoding the large subunit of alkyl hydroperoxide reductase. Reporter gene studies showed that iron regulation of ahpC and katA is achieved at the transcriptional level. Insertional mutagenesis of the ahpC gene resulted in an increased sensitivity to oxidative stresses caused by cumene hydroperoxide and exposure to atmospheric oxygen, while resistance to hydrogen peroxide was not affected. The C. jejuni AhpC protein is an important determinant of the ability of this microaerophilic pathogen to survive oxidative and aerobic stress.


Subject(s)
Campylobacter jejuni/enzymology , Gene Expression Regulation, Bacterial/drug effects , Iron/pharmacokinetics , Oxidative Stress/physiology , Oxidoreductases/metabolism , Peroxidases , Aerobiosis , Bacterial Proteins/genetics , Base Sequence , Campylobacter jejuni/genetics , Campylobacter jejuni/growth & development , DNA Mutational Analysis , Gene Expression Regulation, Enzymologic/drug effects , Genes, Reporter , Molecular Sequence Data , Peptides/genetics , Peroxiredoxins , Sequence Homology, Amino Acid , Transcription, Genetic/drug effects
9.
J Bacteriol ; 181(10): 3298-302, 1999 May.
Article in English | MEDLINE | ID: mdl-10322038

ABSTRACT

Campylobacter jejuni colonizes the intestines of domestic and wild animals and is a common cause of human diarrheal disease. We identified a two-component regulatory system, designated the RacR-RacS (reduced ability to colonize) system, that is involved in a temperature-dependent signalling pathway. A mutation of the response regulator gene racR reduced the organism's ability to colonize the chicken intestinal tract and resulted in temperature-dependent changes in its protein profile and growth characteristics.


Subject(s)
Bacterial Proteins/genetics , Campylobacter jejuni/growth & development , Animals , Bacterial Proteins/biosynthesis , Bacterial Proteins/physiology , Campylobacter jejuni/cytology , Campylobacter jejuni/enzymology , Campylobacter jejuni/genetics , Cell Division , Chickens/microbiology , Cloning, Molecular , Colony Count, Microbial , Digestive System/microbiology , Electrophoresis, Gel, Two-Dimensional , Gene Expression Regulation, Bacterial , Histidine Kinase , Isoelectric Point , Molecular Sequence Data , Molecular Weight , Mutagenesis, Insertional , Open Reading Frames/genetics , Operon/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Regulon/genetics , Repressor Proteins/genetics , Repressor Proteins/physiology , Signal Transduction , Temperature , Trans-Activators/genetics , Trans-Activators/physiology
10.
Appl Environ Microbiol ; 65(4): 1610-8, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10103258

ABSTRACT

Utilization of ferrioxamines as sole sources of iron distinguishes Salmonella enterica serotypes Typhimurium and Enteritidis from a number of related species, including Escherichia coli. Ferrioxamine supplements have therefore been used in preenrichment and selection media to increase the bacterial growth rate while selectivity is maintained. We characterized the determinants involved in utilization of ferrioxamines B, E, and G by S. enterica serotype Typhimurium by performing siderophore cross-feeding bioassays. Transport of all three ferric siderophores across the outer membrane was dependent on the FoxA receptor encoded by the Fur-repressible foxA gene. However, only the transport of ferrioxamine G was dependent on the energy-transducing protein TonB, since growth stimulation of a tonB strain by ferrioxamines B and E was observed, albeit at lower efficiencies than in the parental strain. Transport across the inner membrane was dependent on the periplasmic binding protein-dependent ABC transporter complex comprising FhuBCD, as has been reported for other hydroxamate siderophores of enteric bacteria. The distribution of the foxA gene in the genus Salmonella, as indicated by DNA hybridization studies and correlated with the ability to utilize ferrioxamine E, was restricted to subspecies I, II, and IIIb, and this gene was absent from subspecies IIIa, IV, VI, and VII (formerly subspecies IV) and Salmonella bongori (formerly subspecies V). S. enterica serotype Typhimurium mutants with either a transposon insertion or a defined nonpolar frameshift (+2) mutation in the foxA gene were not able to utilize any of the three ferrioxamines tested. A strain carrying the nonpolar foxA mutation exhibited a significantly reduced ability to colonize rabbit ileal loops compared to the foxA+ parent. In addition, a foxA mutant was markedly attenuated in mice inoculated by either the intragastric or intravenous route. Mice inoculated with the foxA mutant were protected against subsequent challenge by the foxA+ parent strain.


Subject(s)
Escherichia coli Proteins , Ferric Compounds/metabolism , Receptors, Cell Surface , Salmonella typhimurium/metabolism , Siderophores/metabolism , Amino Acid Sequence , Animals , Bacterial Outer Membrane Proteins/genetics , Bacterial Outer Membrane Proteins/metabolism , Base Sequence , Biological Transport , Deferoxamine/metabolism , Genes, Bacterial , Ileum/microbiology , Ileum/physiopathology , Iron Chelating Agents/metabolism , Mice , Molecular Sequence Data , Mutation , Peptides, Cyclic/metabolism , Rabbits , Salmonella Infections, Animal/microbiology , Salmonella typhimurium/genetics , Salmonella typhimurium/pathogenicity , Sequence Analysis, DNA
12.
J Bacteriol ; 180(20): 5291-8, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9765558

ABSTRACT

The expression of iron-regulated systems in gram-negative bacteria is generally controlled by the Fur protein, which represses the transcription of iron-regulated promoters by using Fe2+ as a cofactor. Mutational analysis of the Campylobacter jejuni fur gene was carried out by generation of a set of mutant copies of fur which had a kanamycin or chloramphenicol resistance gene introduced into the regions encoding the N and C termini of the Fur protein. The mutated genes were recombined into the C. jejuni NCTC 11168 chromosome, and putative mutants were confirmed by Southern hybridization. C. jejuni mutants were obtained only when the resistance genes were transcribed in the same orientation as the fur gene. The C. jejuni fur mutant grew slower than the parental strain. Comparison of protein profiles of fractionated C. jejuni cells grown in low- or high-iron medium indicated derepressed expression of three iron-regulated outer membrane proteins with molecular masses of 70, 75, and 80 kDa. Characterization by N-terminal amino acid sequencing showed the 75-kDa protein to be identical to CfrA, a Campylobacter coli siderophore receptor homologue, whereas the 70-kDa protein was identified as a new siderophore receptor homologue. Periplasmic fractions contained four derepressed proteins with molecular masses of 19, 29, 32, and 36 kDa. The 19-kDa protein has been previously identified, but its function is unknown. The cytoplasmic fraction contained two iron-repressed and two iron-induced proteins with molecular masses of 26, 55, 31, and 40 kDa, respectively. The two iron-repressed proteins have been previously identified as the oxidative stress defense proteins catalase (KatA) and alkyl hydroperoxide reductase (AhpC). AhpC and KatA were still iron regulated in the fur mutant, suggesting the presence of Fur-independent iron regulation. Further analysis of the C. jejuni iron and Fur regulons by using two-dimensional gel electrophoresis demonstrated the total number of iron- and Fur-regulated proteins to be lower than for other bacterial pathogens.


Subject(s)
Bacterial Proteins/genetics , Campylobacter jejuni/genetics , Gene Expression Regulation, Bacterial , Iron/pharmacology , Mutation , Repressor Proteins/genetics , Amino Acid Sequence , Dose-Response Relationship, Drug , Genes, Regulator , Molecular Sequence Data , Mutagenesis, Site-Directed , Regulon , Sequence Homology, Amino Acid
13.
Trends Microbiol ; 5(3): 96-102, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9080607

ABSTRACT

The enteric pathogens Campylobacter jejuni and Campylobacter coli are a major cause of infectious diarrhoea. Their ability to adhere to human epithelial cells is ubiquitous and their propensity to invade cells is also well documented and requires motility and de novo protein synthesis, as well as several host factors. The molecular basis of the interaction between campylobacters and host cells is only beginning to be elucidate. The characteristics of this interaction promise to be interesting and may provide new insights into host-pathogen interactions in other enteric diseases.


Subject(s)
Campylobacter coli/immunology , Campylobacter jejuni/immunology , Campylobacter Infections/physiopathology , Campylobacter coli/pathogenicity , Campylobacter jejuni/pathogenicity , Cell Line , Epithelial Cells , Humans , Macrophages/immunology , Monocytes/immunology , Neutrophils/immunology
14.
Microb Pathog ; 21(4): 299-305, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8905618

ABSTRACT

Caveolae are plasma membrane invaginations found in a variety of mammalian cells and are implicated in clathrin-independent endocytosis and signal transduction. Here we show that pretreatment of Caco-2 cell monolayers with filipin III, which disrupts caveolae by chelating cholesterol, significantly reduces the ability of Campylobacter jejuni to enter these cells. Furthermore inhibitors of host protein tyrosine phosphorylation, the phosphatidylinositol-3 kinase (Pl 3-kinase) inhibitor wortmannin, and cholera toxin, all significantly reduced invasion of Caco-2 cells by C. jejuni.


Subject(s)
Campylobacter jejuni/pathogenicity , Endocytosis/drug effects , Intestines/microbiology , Androstadienes/pharmacology , Caco-2 Cells , Cell Membrane , Chelating Agents/pharmacology , Cholera Toxin/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Filipin/pharmacology , Humans , Intestines/cytology , Signal Transduction , Staurosporine/pharmacology , Wortmannin
16.
J Bacteriol ; 176(18): 5852-6, 1994 Sep.
Article in English | MEDLINE | ID: mdl-8083178

ABSTRACT

The Fur protein of Escherichia coli represses transcription from Fur-responsive genes in an iron-dependent manner. We have demonstrated a Fur-like iron-responsive genetic regulatory activity operating in Campylobacter jejuni by using a chloramphenicol acetyl transferase reporter gene separated from its promoter by a synthetic Fur-responsive operator. A fur-like gene has been cloned from C. jejuni by partial functional complementation of an E. coli fur mutation. Sequence analysis has shown that, at the amino acid level, the C. jejuni Fur protein is 35% identical with its E. coli counterpart.


Subject(s)
Bacterial Proteins/genetics , Campylobacter jejuni/genetics , Genes, Bacterial/genetics , Iron/pharmacology , Repressor Proteins/genetics , Sequence Homology, Amino Acid , Amino Acid Sequence , Base Sequence , Chloramphenicol O-Acetyltransferase/genetics , Cloning, Molecular , Gene Expression Regulation, Bacterial/drug effects , Genes, Reporter/genetics , Genetic Complementation Test , Molecular Sequence Data , Operator Regions, Genetic/genetics , Sequence Alignment , Sequence Analysis, DNA
18.
Infect Immun ; 62(4): 1480-3, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8132356

ABSTRACT

The potential for reacquisition of ctxA genes by attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR was examined by performing a series of mating experiments under a variety of in vivo and in vitro conditions. We found no evidence that CVD 103-HgR could reacquire ctxA genes from wild-type V. cholerae O1 strains. However, if the donor V. cholerae O1 strains were genetically manipulated to add genes that allow chromosomal gene transfer, then ctxA sequences could be acquired by CVD 103-HgR. The minimal excretion of CVD 103-HgR by vaccinees and the refractoriness to reacquisition of ctxA sequences suggest that this well-tolerated, highly immunogenic live oral cholera vaccine will have a minimal environmental impact.


Subject(s)
Cholera Vaccines/genetics , Enterotoxins/genetics , Vibrio cholerae/genetics , Gene Transfer Techniques , Vaccines, Attenuated/genetics , Vibrio cholerae/pathogenicity
19.
Infect Immun ; 61(11): 4885-7, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8406889

ABSTRACT

Infection of rabbit ileal loops with inflammatory Campylobacter jejuni strains caused elevation of cyclic AMP, prostaglandin E2, and leukotriene B4 levels in tissue and fluids. Incubation of cultured Caco-2 cells with loop fluids caused elevated cellular cyclic AMP levels, an effect which was inhibited by antiserum against prostaglandin E2.


Subject(s)
Campylobacter Infections/metabolism , Campylobacter jejuni/pathogenicity , Cyclic AMP/physiology , Dinoprostone/physiology , Intestinal Secretions/metabolism , Leukotriene B4/physiology , Animals , Campylobacter Infections/microbiology , Cell Line , Humans , Ileum/microbiology , Rabbits
20.
FEMS Microbiol Lett ; 111(1): 15-21, 1993 Jul 15.
Article in English | MEDLINE | ID: mdl-8359676

ABSTRACT

Attenuated Vibrio cholerae O1 vaccine strains lacking the gene encoding the A subunit of cholera toxin have proven efficacious in preventing experimental cholera. As these strains move from closed, contained testing environments to large-scale field trials, a readily assayable phenotypic trait to distinguish a vaccine strain from wild-type V. cholerae O1 is desirable. We have constructed three derivatives of the attenuated V. cholerae strain CVD 103 which carry a mercury resistance or urease marker in the hlyA gene. CVD 103-HgR was constructed using a protracted marker-exchange procedure; this strain was found to have somewhat lowered colonisation efficiency in infant mice in comparison to its parent strain, CVD 103. The insertion of the resistance marker was repeated using a suicide vector system; CVD 103-HgR2 was found to colonise infant mice as efficiently as CVD 103. Strain CVD 103-UR, in which sequences encoding urease were inserted using a suicide vector, also colonised infant mice as well as CVD 103. The genetically marked strains CVD 103-HgR, CVD 103-HgR2 and CVD 103-UR form the basis for a generation of defined oral vaccines that may give single-dose, long-lasting protection to populations at risk from cholera.


Subject(s)
Cholera Toxin/genetics , Vaccines, Attenuated/genetics , Vibrio cholerae/genetics , Vibrio cholerae/immunology , Viral Vaccines/genetics , Animals , Cholera/microbiology , Diarrhea/microbiology , Drug Resistance, Microbial/genetics , Escherichia coli/genetics , Genetic Markers , Genetic Vectors , Macromolecular Substances , Mice , Mutagenesis, Insertional , Rabbits , Vaccines, Attenuated/biosynthesis , Vibrio cholerae/pathogenicity , Viral Vaccines/biosynthesis , Virulence
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