The host-adapted human pathogen Neisseria gonorrhoeae is the causative agent of gonorrhoea. Consistent with its proposed evolution from an ancestral commensal bacterium, N. gonorrhoeae has retained ...features that are common in commensals, but it has also developed unique features that are crucial to its pathogenesis. The continued worldwide incidence of gonorrhoeal infection, coupled with the rising resistance to antimicrobials and the difficulties in controlling the disease in developing countries, highlights the need to better understand the molecular basis of N. gonorrhoeae infection. This knowledge will facilitate disease prevention, surveillance and control, improve diagnostics and may help to facilitate the development of effective vaccines or new therapeutics. In this Review, we discuss sex-related symptomatic gonorrhoeal disease and provide an overview of the bacterial factors that are important for the different stages of pathogenesis, including transmission, colonization and immune evasion, and we discuss the problem of antibiotic resistance.
The 10 human-restricted Neisseria species all colonize mucosal surfaces, but show a spectrum of pathogenicity. The commensal Neisseria do not normally cause pathology, while the two pathogenic ...species, Neisseria meningitidis and Neisseria gonorrhoeae, straddle the border between commensalism and pathogenicity. Why the pathogenic Neisseria continue to mediate host damage after thousands of years of co-evolution with their human host, and why the commensal species have not acquired the ability to damage the host, if this capability provides a selective advantage, is not understood. One way the pathogenic species are different from the commensal species is by their ability to induce PMN inflammation, which is dependent on the site of colonization. I discuss how the site of colonization dictates whether copious inflammation occurs with both pathogenic species. I put forth a model that posits that an ancestor of both pathogenic species changed colonization site from the oral cavity to the genital tract of a human or humanoid and had to evolve multiple, new traits — to induce PMN inflammation and avoid adaptive immunity — to allow efficient sexual transmission. This model predicts that PMN inflammation produces the serious sequelae of gonorrhea and increases the probability that N. meningitidis might exit the oral cavity to produce systemic disease. In both cases, the pathology produced by these host-adapted species is an unintended by product of the inflammation but host damage does not provide any selective advantage for these organisms.
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•There are several human-restricted Neisseria species that show a gradient of pathogenicity.•The commensal Neisseria rarely cause damage to the host. Neisseria meningiditis only causes morbidity and mortality when it leaves the nasal pharynx. Neisseria gonorrhoeae more readily induces polymorphonuclear leukocyte (PMN) inflammation and colonization of alternate anatomical sites results in host damage.•In contrast to the other Neisseria, colonization of N. gonorrhea that does not elicit symptoms is classified as asymptomatic infection rather than commensal colonization.•The level of PMN inflammation is influenced by the Neisseria species involved and the site of colonization. Whether PMNs are always recruited during the colonization of different sites is not known.•The two pathogenic Neisseria arose from a common ancestor.•A model for the evolution of the pathogenic species is proposed where a common, progenitor, commensal organism transferred from the oral cavity to the genital tract of a human or humanoid. In that location, there was strong selection to evolve the ability to induce PMN inflammation as a way to enable efficient sexual transmission.
The strict human pathogen Neisseria gonorrhoeae can utilize homologous recombination to generate antigenic variability in targets of immune surveillance. To evade the host immune response, N. ...gonorrhoeae promotes high frequency gene conversion events between many silent pilin copies and the expressed pilin locus (pilE), resulting in the production of variant pilin proteins. Previously, we identified a guanine quartet (G4) structure localized near pilE that is required for the homologous recombination reactions leading to pilin antigenic variation (Av). In this work, we demonstrate that inactivating the promoter of a small non-coding RNA (sRNA) that initiates within the G4 forming sequence blocks pilin Av. The sRNA promoter is conserved in all sequenced gonococcal strains, and mutations in the predicted transcript downstream of the G4 forming sequence do not alter pilin Av. A mutation that produces a stronger promoter or substitution of the pilE G4-associated sRNA promoter with a phage promoter (when the phage polymerase was expressed) produced wild-type levels of pilin Av. Altering the direction and orientation of the pilE G4-associated sRNA disrupted pilin Av. In addition, expression of the sRNA at a distal site on the gonococcal chromosome in the context of a promoter mutant did not support pilin Av. We conclude that the DNA containing the G-rich sequence can only form the G4 structure during transcription of this sRNA, thus providing a unique molecular step for the initiation of programmed recombination events.
Advances in understanding mechanisms of nucleic acids have revolutionized molecular biology and medicine, but understanding of nontraditional nucleic acid conformations is less developed. The guanine ...quadruplex (G4) alternative DNA structure was first described in the 1960s, but the existence of G4 structures (G4-S) and their participation in myriads of biological functions are still underappreciated. Despite many tools to study G4s and many examples of roles for G4s in eukaryotic molecular processes and issues with uncontrolled G4-S formation, there is relatively little knowledge about the roles of G4-S in viral or prokaryotic systems. This review summarizes the state of the art with regard to G4-S in eukaryotes and their potential roles in human disease before discussing the evidence that G4-S have equivalent importance in affecting viral and bacterial life.
Effective interdisciplinary communication of imaging findings is vital for patient care, as referring physicians depend on the contained information for the decision-making and subsequent treatment. ...Traditional radiology reports contain non-structured free text and potentially tangled information in narrative language, which can hamper the information transfer and diminish the clarity of the report. Therefore, this study investigates whether newly developed structured reports (SRs) of prostate magnetic resonance imaging (MRI) can improve interdisciplinary communication, as compared to non-structured reports (NSRs).
50 NSRs and 50 SRs describing a single prostatic lesion were presented to four urologists with expert level experience in prostate cancer surgery or targeted MRI TRUS fusion biopsy. They were subsequently asked to plot the tumor location in a 2-dimensional prostate diagram and to answer a questionnaire focusing on information on clinically relevant key features as well as the perceived structure of the report. A validated scoring system that distinguishes between "major" and "minor" mistakes was used to evaluate the accuracy of the plotting of the tumor position in the prostate diagram.
The mean total score for accuracy for SRs was significantly higher than for NSRs (28.46 range 13.33-30.0 vs. 21.75 range 0.0-30.0, p < 0.01). The overall rates of major mistakes (54% vs. 10%) and minor mistakes (74% vs. 22%) were significantly higher (p < 0.01) for NSRs than for SRs. The rate of radiologist re-consultations was significantly lower (p < 0.01) for SRs than for NSRs (19% vs. 85%). Furthermore, SRs were rated as significantly superior to NSRs in regard to determining the clinical tumor stage (p < 0.01), the quality of the summary (4.4 vs. 2.5; p < 0.01), and overall satisfaction with the report (4.5 vs. 2.3; p < 0.01), and as more valuable for further clinical decision-making and surgical planning (p < 0.01).
Structured reporting of prostate MRI has the potential to improve interdisciplinary communication. Through SRs, expert urologists were able to more accurately assess the exact location of single prostate cancer lesions, which can facilitate surgical planning. Furthermore, structured reporting of prostate MRI leads to a higher satisfaction level of the referring physician.
Abstract
Pathogenic microorganisms employ numerous molecular strategies in order to delay or circumvent recognition by the immune system of their host. One of the most widely used strategies of ...immune evasion is antigenic variation, in which immunogenic molecules expressed on the surface of a microorganism are continuously modified. As a consequence, the host is forced to constantly adapt its humoral immune response against this pathogen. An antigenic change thus provides the microorganism with an opportunity to persist and/or replicate within the host (population) for an extended period of time or to effectively infect a previously infected host. In most cases, antigenic variation is caused by genetic processes that lead to the modification of the amino acid sequence of a particular antigen or to alterations in the expression of biosynthesis genes that induce changes in the expression of a variant antigen. Here, we will review antigenic variation systems that rely on homologous DNA recombination and that are found in a wide range of cellular, human pathogens, including bacteria (such as Neisseria spp., Borrelia spp., Treponema pallidum, and Mycoplasma spp.), fungi (such as Pneumocystis carinii) and parasites (such as the African trypanosome Trypanosoma brucei). Specifically, the various DNA recombination–based antigenic variation systems will be discussed with a focus on the employed mechanisms of recombination, the DNA substrates, and the enzymatic machinery involved.
In this review, gene conversion mechanisms are described that induce antigenic variation in a wide range of human cellular pathogens, including bacteria, fungi and parasites.
Neisseria gonorrhoeae and Neisseria meningitidis are closely related organisms that cause the sexually transmitted infection gonorrhea and serious bacterial meningitis and septicemia, respectively. ...Both species possess multiple mechanisms to alter the expression of surface-exposed proteins through the processes of phase and antigenic variation. This potential for wide variability in surface-exposed structures allows the organisms to always have subpopulations of divergent antigenic types to avoid immune surveillance and to contribute to functional variation. Additionally, the Neisseria are naturally competent for DNA transformation, which is their main means of genetic exchange. Although bacteriophages and plasmids are present in this genus, they are not as effective as DNA transformation for horizontal genetic exchange. There are barriers to genetic transfer, such as restriction-modification systems and CRISPR loci, that limit particular types of exchange. These host-restricted pathogens illustrate the rich complexity of genetics that can help define the similarities and differences of closely related organisms.
Pathogens can use DNA recombination to promote antigenic variation (Av) of surface structures to avoid immune detection. We identified a cis-acting DNA sequence near the antigenically variable pilin ...locus of the human pathogen, Neisseria gonorrhoeae. This 16--base pair guanine (G)--rich sequence was required for pilin Av and formed a guanine quartet (G4) structure in vitro. Individual mutations that disrupted the structure also blocked pilin Av and prevented nicks required for recombination from occurring within the G4 region. A compound that binds and stabilizes G4 structures also inhibited pilin Av and prevented nicks from occurring on the G-rich strand. This site constitutes a recombination initiation sequence/structure that directs gene conversion to a specific chromosomal locus.
Influence of mean stress on fatigue life of the austenitic stainless steel 316 L in air and light water environments (boiling water reactor/hydrogen water chemistry) at 288 °C was determined with a ...series of tests carried out in load-control mode. Fatigue life was found to increase with application of compressive and tensile mean stress in air and light water reactor environments. Secondary hardening was regarded as the main reason for this behavior. A modified Smith-Watson-Topper (SWT) model was considered to account for mean stress and was shown to predict fatigue life accurately in air and water environments. The reduction of fatigue life in water environment, determined with the SWT curves, was about 2.5. Observations of the end-of-life dislocation arrangements by transmission electron microscopy showed that the dislocation microstructure depends essentially on plastic strain amplitude, which in turn is strongly correlated to stress amplitude and mean stress. The microstructures were found consistent with those usually observed after strain-controlled experiments. At rather low plastic strain amplitudes, corduroy structure consisting of small dislocation loops was observed. Acting as significant obstacle to dislocation motion, corduroy structure affects overall dislocation mobility therefore contributing to notable secondary cyclic hardening.
CRISPR interference confers adaptive, sequence-based immunity against viruses and plasmids and is specified by CRISPR RNAs (crRNAs) that are transcribed and processed from spacer-repeat units. ...Pre-crRNA processing is essential for CRISPR interference in all systems studied thus far. Here, our studies of crRNA biogenesis and CRISPR interference in naturally competent Neisseria spp. reveal a unique crRNA maturation pathway in which crRNAs are transcribed from promoters that are embedded within each repeat, yielding crRNA 5′ ends formed by transcription and not by processing. Although crRNA 3′ end formation involves RNase III and trans-encoded tracrRNA, as in other type II CRISPR systems, this processing is dispensable for interference. The meningococcal pathway is the most streamlined CRISPR/Cas system characterized to date. Endogenous CRISPR spacers limit natural transformation, which is the primary source of genetic variation that contributes to immune evasion, antibiotic resistance, and virulence in the human pathogen N. meningitidis.
•Unlike previously described CRISPRs, each Neisseria repeat carries its own promoter•Pre-crRNA processing is dispensable for CRISPR interference in Neisseria spp.•CRISPR interference blocks natural transformation in the pathogen N. meningitidis•Neisseria CRISPR/Cas systems are the most streamlined observed to date
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