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PubMed2001

Differential regulation of Bvg-activated virulence factors plays a role in Bordetella pertussis pathogenicity.

Bordetella pertussis, the causative agent of whooping cough, regulates expression of many virulence factors via a two-component signal transduction system encoded by the bvgAS regulatory locus. It has been shown by transcription activation kinetics that several of the virulence factors are differentially regulated. fha is transcribed within 10 min following a bvgAS-inducing signal, while prn is transcribed after 1 h and ptx is not transcribed until 2 to 4 h after induction. These genes therefore represent early, intermediate, and late classes of bvg-activated promoters, respectively. Although there have been many insightful studies into the mechanisms of BvgAS-mediated regulation, the role that differential regulation of virulence genes plays in B. pertussis pathogenicity has not been characterized. We provide evidence that alterations to the promoter regions of bvg-activated genes can alter the kinetic pattern of expression of these genes without changing steady-state transcription levels. In addition, B. pertussis strains containing these promoter alterations that express either ptx at an early time or fha at a late time demonstrate a significant reduction in their ability to colonize respiratory tracts in an intranasal mouse model of infection. These data suggest a role for differential regulation of bvg-activated genes, and therefore for the BvgAS regulatory system, in the pathogenicity of B. pertussis.

Animals↗
PubMed2003

Molecular genetics of Porphyromonas gingivalis: gingipains and other virulence factors.

Porphyromonas gingivalis is a black-pigmented anaerobic gram-negative bacterium that is a major pathogen of chronic adult periodontitis, an inflammatory disease of tooth-supporting tissues. P. gingivalis possesses a number of potential virulence factors. Among them, cell-surface-associated and secreted proteinases such as Arg-gingipain and Lys-gingipain have received much attention because they can degrade various host proteins and cause inflammation. Molecular genetic analysis is extremely powerful to evaluate the significance of each virulence factor in a pathogenic microorganism. This review will describe the introduction of molecular genetics to analysis of pathogenesis of P. gingivalis and the findings that have been obtained using knockout mutants of various potential virulence factors, especially proteinases.

Adhesins, Bacterial↗
PubMed2003

Molecular mechanism of action of major Helicobacter pylori virulence factors.

Although Helicobacter pylori infects 50% of the total human population, only a small fraction of the infected people suffer from severe diseases like peptic ulcers and gastric adenocarcinoma. H. pylori strains, host genotypes and environmental factors play important role in deciding the extent and severity of the gastroduodenal diseases. The bacteria has developed a unique set of virulence factors to survive in the extreme ecological niche of human stomach. Together these virulence factors make H. pylori one of the most successful human pathogenic bacteria colonizing more than half of the human population. Understanding the mechanism of action of the major H. pylori virulence factors will shed light into the molecular basis of its pathogenicity.

Adhesins, Bacterial↗
PubMed1998

Extracellular phospholipases as universal virulence factor in pathogenic fungi.

Microbial pathogens use a number of genetic strategies to invade the host and cause infection. These common themes are found throughout microbial virulence factors. Secretion of enzymes, such as phospholipase, has been proposed as one of these themes which is used by bacteria, parasite, and pathogenic fungi. The role of extracellular phospholipase as a potential virulence factor in pathogenic fungi, including Candida albicans, Cryptococcus neoformans and Aspergillus has gained credence recently. In this address data implicating phospholipase as a virulence factor in Cryptococcus neoformans and Aspergillus fumigatus will be presented. This will be followed by a more detailed description of our molecular and biochemical approaches we used to more definitively delineate the role of phospholipase in the virulence of C. albicans. First, we purified the phospholipase B protein, the dominant phospholipase secreted by C. albicans, obtained the amino acid sequence of its N-terminus and an internal peptide fragment, and used this information to clone the gene encoding the protein using a PCR-based approach. Nucleotide sequence analysis revealed an ORF of 1818 bp that predicted for a pre-protein of 605 amino acid residues. The deduced amino acid sequences of the cloned gene (PLB 1) showed 42.3%, 45%, and 47.8% overall sequence identity, with the reported sequences of phospholipase B cloned from Penicillium notatum, Saccharomyces cerevisiae, and Saccharomyces rosei, respectively. Second, using targeted gene disruption, URA blaster, we created C. albicans null mutants which failed to secrete phospholipase B. Third, we tested the ability of these isogenic strain pairs to cause lethality using a murine model of hematogenously disseminated candidiasis. Our data demonstrate that the parent phospholipase-producing strain caused more fatality in mice, while the null phospholipase-deficient strain was avirulent. Importantly, the parent and null mutants had similar growth and germination rates. These data prove that phospholipase B is essential for candidal virulence, and pave the way for studies directed at determining the mechanism/s through which phospholipase modulate candidal virulence. Understanding phospholipase as a common theme in fungal pathogenicity is critical for developing new antifungal strategies based on anti-virulence.

Animals↗
PubMed2003

The ABC transporter MgAtr4 is a virulence factor of Mycosphaerella graminicola that affects colonization of substomatal cavities in wheat leaves.

The role in virulence of the ATP-binding cassette (ABC) transporters MgAtr1, MgAtr2, MgAtr3, MgAtr4, and MgAtr5 from Mycosphaerella graminicola was analyzed by gene disruption or replacement on seedlings of the susceptible wheat cultivar Obelisk. Disruption strains of MgAtr1 and MgAtr2 and replacement strains of MgAtr3 and MgAtr5 displayed the same phenotype as control strains, while virulence of the MgAtr4 disruption strains was significantly reduced. This reduction in virulence was independent of the wheat cultivar used. Histopathological analysis of the infection process revealed that MgAtr4 disruption strains colonize substomatal cavities less efficiently and display reduced intercellular growth in the apoplast of wheat leaves. In vitro growth experiments in different media showed no fitness penalty associated with the disruption of MgAtr4. Expression analysis demonstrated that transcripts of the constitutively expressed gene CYP51 encoding the fungal-specific cytochrome P450 sterol 14alpha-demethylase from M. graminicola were not detectable in interaction RNA from wheat infected with MgAtr4 disruption strains, thus confirming the reduced intercellular growth of these strains. The results indicate that MgAtr4 is a virulence factor of M. graminicola during pathogenesis on wheat and may function in protection against fungitoxic compounds present around the substomatal cavities of wheat leaves. MgAtr4 is the first virulence factor cloned from this important plant pathogen.

ATP-Binding Cassette Transporters↗
PubMed2003

From nose to lung: the regulation behind Streptococcus pneumoniae virulence factors.

Streptococcus pneumoniae probably possesses a redundant set of factors required for colonization of the nasopharynx and invasive disease, because of its strict relationship with its human host and relatively small genome size (approximately 2.1 Mb). Nevertheless, transcriptional regulation of genes encoding factors required for in vivo growth is predicted to be important on two fronts: in the transition from carriage to invasive disease and within different microniches of the nasopharynx. The importance of both serotype-specific and host tissue-specific virulence factors during infection and disease has been highlighted by the recent identification of novel virulence factors in this organism coupled with the release of complete genome sequences from two strains. These studies add to the foundation of knowledge of classical S. pneumoniae virulence factors such as polysaccharide capsule and pneumolysin, which have well-documented roles in pathogenesis.

Bacterial Proteins↗
PubMed1992

Lack of virulence factors in Escherichia coli strains of enteropathogenic serogroups isolated from water.

Thirty-eight Escherichia coli strains belonging to 14 human enteropathogenic serogroups were isolated from 33 of 208 water samples studied. No virulence factor or virulence-related gene sequences were found in any of the 38 strains analyzed. The results point out the importance of detecting specific virulence factors before incriminating water as a source of human diarrhea.

Escherichia coli↗
PubMed2000

Human response to Escherichia coli O157:H7 infection: antibodies to secreted virulence factors.

Vaccination has been proposed for the prevention of disease due to enterohemorrhagic Escherichia coli (EHEC), but the immune response following human infection, including the choice of potential antigens, has not been well characterized. To study this, sera were obtained from five pediatric patients with acute diarrhea caused by E. coli O157:H7 0, 8, and 60 days after hospitalization. These sera were used to examine the immune response to four different EHEC virulence factors: Tir (translocated intimin receptor, which is inserted into the host cell membrane), intimin (bacterial outer membrane protein which binds to Tir), EspA (secreted protein which forms filamentous structures on EHEC surface), and EspB (inserted into the host membrane and cytoplasm). The response to O157:H7 lipopolysaccharide was also examined. Sera were assayed against purified recombinant proteins using immunoblot analysis and by enzyme-linked immunosorbent assay to determine the sera's titers to each of the antigens in all patients. We found that there was little reaction to EspA, EspB, and intimin in the acute-phase sera, although there was some reactivity to Tir. By day 8, titers of antibody to all four virulence factors were present in all patients, with a very strong response against Tir (up to a titer of 1:256,000), especially in hemolytic-uremic syndrome patients, and lesser strong responses to the other three antigens. The titer to the antigens 60 days after hospitalization was decreased but was still highest for Tir. These results suggest that there is a strong immune response to Tir, and to a lesser extent to the other three virulence factors, following EHEC disease, indicating that these bacterial molecules are potential vaccine candidates for preventing EHEC disease. They also suggest that bacterial virulence factors that are inserted into host cells during infection by type III secretion systems (Tir or EspB) are still recognized by the host immune response.

Adhesins, Bacterial↗
PubMed1996

Differential contribution of Yersinia enterocolitica virulence factors to evasion of microbicidal action of neutrophils.

The differential contribution of the virulence factors invasin, protein tyrosine phosphatase (YopH), cytotoxin (YopE), and adhesin (YadA) of Yersinia enterocolitica to evasion of the antibacterial activities of polymorphonuclear leukocytes (PMNs) (oxidative burst, phagocytosis, killing) was analyzed. We constructed virulence gene knockout mutants and a novel two-plasmid system allowing production and secretion of individual virulence factors. Wild-type Y. enterocolitica WA-314 harboring the virulence plasmid pYV08 resisted phagocytosis and killing by PMNs. Moreover, strain WA-314 was able to inhibit the neutrophil oxidative burst upon stimulation with opsonized zymosan independently on preincubation with normal human serum or YadA-specific serum. These phenotypic properties of strain WA-314 were differentially affected when mutants impaired in YadA production or Yop secretion were used. A more detailed analysis revealed that YopH plays the dominant role in suppression of the antibacterial action of PMNs without damaging the cells. The YopH suppressing effect could be enhanced by coproduction of YopE and YadA. The contribution of YadA is attributed to the adhesin function promoting interaction with PMNs under both opsonizing and nonopsonizing conditions. In contrast, invasin seems to mediate only opsonin-independent interaction with PMNs. Taken together, our results demonstrate that YopH, YopE, and YadA act in concert towards neutrophil attack to enable extracellular survival of Y. enterocolitica in host tissue.

Adhesins, Bacterial↗
PubMed1986

The role of K antigens as virulence factors in Klebsiella.

The importance of K antigen of Klebsiella as a virulence factor was studied in nine pairs of K+ and K- strains, each pair isogenic apart from the presence of K antigen. Loss of K antigen by nine K+ strains resulted in the reduced virulence of their K- variants in a mouse-skin model. This reduced virulence of K- strains for mice may be explained in all strains by a higher degree of phagocytosis as measured by chemiluminescence response of human polymorphonuclear leukocytes (PMNL) and in most strains by enhanced killing by either human PMNL or human serum or both. Although the protective role of the K antigen in serum-induced killing and killing by PMNL was generally evident, our results also suggested that other virulence factors were sometimes involved.

Animals↗
PubMed2004

Genomic subtraction for the identification of putative new virulence factors of an avian pathogenic Escherichia coli strain of O2 serogroup.

To identify putative new virulence factors of avian pathogenic Escherichia coli (APEC) strains, a genomic subtraction was performed between the APEC strain MT512 and the non-pathogenic E. coli strain of avian origin EC79. Seventeen DNA fragments were cloned that were specific for the APEC strain. Among them, nine were identified that were more frequent among pathogenic than non-pathogenic isolates in a collection of 67 avian E. coli. Chromosome or plasmid location, and the nucleotide sequence of these nine fragments were characterized. Four fragments were plasmid-located. The nucleotide sequence of two of them exhibited identity with the sequence of the RepF1B replicon of E. coli plasmids, and the amino-acid deduced sequences from the two other fragments exhibited similarity to the products of genes sitA of Salmonella Typhimurium and iroD of E. coli, which are involved in iron metabolism. Of the five chromosome-located fragments, three were predicted to encode parts of proteins that were significantly homologous to previously described proteins: TktA (transketolase) of Haemophilus influenzae, a FruA (fructokinase) homologue of Listeria innocua and Gp2 (large terminal subunit) of phage 21. The putative products of the two other chromosome-located fragments were homologous to proteins with unknown functions: Z0255 of E. coli strain EDL933 (EHEC) and RatA of Salmonella Typhimurium strain LT2. Both these chromosomal fragments, whose presence is correlated with serogroups O1 and O2 and to the virulence of APEC strains belonging to these serogroups, are good candidates for being part of novel virulence determinants of APEC. Moreover, several fragments were shown to be located close to tRNA selC, asnT or thrW, which suggests they could be part of pathogenicity islands. Six fragments that were shown to be part of whole ORFs present in the APEC strain MT 512 were also present in extra-intestinal pathogenic E. coli (ExPEC) strains of human and animal origin. Thus, the putative novel virulence factors identified in this study could be shared by ExPEC strains of different origins.

Animals↗
PubMed2004

Virulence factors of the coagulase-negative staphylococci.

Coagulase-negative staphylococci (CNS) have gained substantial interest as pathogens involved in nosocomial, particularly catheter-related infections. The pathogenic potential of CNS is mainly due to their capacity to form biofilms on indwelling medical devices. In a biofilm, the bacteria are protected against antibiotics and from attacks by the immune system. The factors contributing to biofilm formation are among the best-studied virulence factors of CNS and comprise factors involved in the adhesion to a catheter surface and in cell accumulation. CNS usually persist in the host in relative silence, but may cause sepsis, for which the recently found inflammatory peptides called phenol-soluble modulins are prime candidates. Many CNS also produce several lipases, proteases, and other exoenzymes, which possibly contribute to the persistence of CNS in the host and may degrade host tissue. We are also beginning to understand how regulators of virulence trigger the expression of virulence factors in CNS. A better conception of the mechanisms underlying the pathogenicity and the frequently encountered antibiotic resistance of CNS may help to develop novel, efficient anti-staphylococcal therapeutics.

Animals↗
PubMed2004

Analysis of virulence factors in cases of enterococcal endocarditis.

Eleven isolates of Enterococcus faecalis causing endocarditis were screened for possible virulence factors with PCR and phenotypic assays. The gene coding for the enterococcal surface protein (esp) was detected in one isolate only, and haemolysin was produced by two isolates. Aggregation substance, biofilm formation and gelatinase were present in seven, nine and eight isolates, respectively. Predisposing factors, particularly hospitalisation and multiple antibiotic therapy, appeared to be more relevant to the development of enterococcal endocarditis following bloodstream infections than the pattern of virulence factors.

Adult↗
PubMed2001

Incidence of virulence factors and antibiotic resistance among Enterococci isolated from food.

The incidence of virulence factors among 48 Enterococcus faecium and 47 Enterococcus faecalis strains from foods and their antibiotic susceptibility were investigated. No strain was resistant to all antibiotics, and for some strains, multiple resistances were observed. Of E. faecium strains, 10.4% were positive for one or more virulence determinants, compared to 78.7% of E. faecalis strains. Strains exhibiting virulence traits were not necessarily positive for all traits; thus, the incidence of virulence factors may be considered to be strain specific.

Anti-Bacterial Agents↗
PubMed2002

hrp genes of Erwinia chrysanthemi 3937 are important virulence factors.

We developed improved virulence assays for Erwinia chrysanthemi 3937 on African violet varieties and devised a new method for the construction of precise bacterial gene knockouts. These methods were tested by constructing mutations in genes suspected to be involved with plant interactions. The virulence of the hrpG and hrcC mutant strains (both gene products presumed to be involved in protein secretion) was greatly reduced on leaves of semitolerant African violet varieties. An hrpN mutant strain produced delayed symptoms on African violet leaves and an hrpN delta pel (delta pel = five major pectate lyase genes deleted) double mutant was nonpathogenic. The hrcC and hrpG mutants did not produce a rapid hypersensitive response (HR) in tobacco, unlike the wild-type bacterium, and the hrpN mutant gave a reduced HR. The results, therefore, establish the importance of hrp genes in the virulence of E. chrysanthemi and their ability to elicit HR on nonhosts. The data also suggest that other effector proteins secreted by the Hrp system are required for full virulence and HR elicitation.

Bacterial Outer Membrane Proteins↗
PubMed2004

Extracellular virulence factors of Streptococcus pneumoniae.

Streptococcus pneumoniae is one of the major human bacterial pathogens. Current prophylactic agents against this pathogen are limited in their protective abilities and the role of therapeutics has been inadequate as resistant strains emerge. The development of new and improved therapies to combat the pneumococcal disease is necessary. In order to accomplish this, an understanding of the interactions between this bacterium and the host tissues is essential. Such interactions largely involve extracellular virulence factors that are expressed by the pathogen to interact with the host. These virulence factors include those based on sugars (glycome-based) as their building blocks, and proteins that are built from amino acids (proteome-based). The first group includes primarily the capsule, teichoic and lipoteichoic acids. The second group is diverse and includes numerous surface proteins that are attached to the cell wall of pneumococci utilizing a variety of methods. For the purpose of this review these surface proteins were divided into three categories, proteins bound to peptidoglycan, those bound to choline residues present on the surface of penumococci, and those bound to the lipids of the cytoplasmic membrane. Both the glycome-based and protein-based virulence factors are described, analyzed, and represented graphically. Whenever possible, structural properties of these molecules were introduced.

Genome, Bacterial↗
PubMed2003

Implication of virulence factors in Escherichia coil O157:H7 pathogenesis.

Since the first documented outbreak of hemorrhagic colitis caused by Escherichia coli O157:H7 in 1982, numerous publications have demonstrated or proposed putative components implicated in the pathogenesis of this gastrointestinal infection. Indeed, Escherichia coli O157:H7 pathogenesis is linked to several potential virulent factors such as verotoxins (or Shiga-like toxins), components implicated in attaching/effacing of microvilli, and the enterohemolysin phenotypes. Defining the precise molecular mechanisms involved in the pathogenesis of E. coli O157:H7 implies detailed comprehension of the virulent factors that provoke a wide range of pathophysiological symptoms. The public health significance of this emerging world-wide menace has been demonstrated by clinical complications during treatment, its low infectious dose, and the severity of clinical manifestations. In this review I describe current knowledge of Escherichia coli O157:H7 pathogenesis with emphasis on known and potential virulent factors.

Animals↗
PubMed2005

Crystal structure of the protease-resistant core domain of Yersinia pestis virulence factor YopR.

Yersinia pestis, the causative agent of the plague, employs a type III secretion system (T3SS) to secrete and translocate virulence factors into to the cytoplasm of mammalian host cells. One of the secreted virulence factors is YopR. Little is known about the function of YopR other than that it is secreted into the extracellular milieu during the early stages of infection and that it contributes to virulence. Hoping to gain some insight into the function of YopR, we determined the crystal structure of its protease-resistant core domain, which consists of residues 38-149 out of 165 amino acids. The core domain is composed of five alpha-helices that display unexpected structural similarity with one domain of YopN, a central regulator of type III secretion in Y. pestis. This finding raises the possibility that YopR may play a role in the regulation of type III secretion.

Amino Acid Sequence↗