Caister Academic Press

Neisseria: Molecular Mechanisms of Pathogenesis

"authoritative reviews" (Microbiology Today)
"a comprehensive update" (Soc. Microbial Ecology and Disease)
"excellent, comprehensive ... valuable and timely ... highly recommended" (Expert Rev. Anti Infect. Ther.)
Publisher: Caister Academic Press
Edited by: Caroline Genco and Lee Wetzler
Boston University School of Medicine, Boston MA 02118, USA
Pages: x + 270
Publication date: January 2010
ISBN: 978-1-904455-51-6
Price: GB £199 or US $250Buy book
Publication date: January 2010
ISBN: 978-1-912530-95-3
Price: US $319Buy ebook
<i>Neisseria</i> book

Neisseria gonorrhoeae and Neisseria meningitidis are Gram-negative diplococci. N. gonorrhoeae is the causative agent of gonorrhoea and is transmitted via sexual contact. N. meningitidis is transmitted via respiratory droplets leading to colonization of the nasopharynx and can cause meningitis and septicemia.

This important reference volume provides research scientists, advanced students, clinicians, and other professionals with a comprehensive update on the current understanding of the molecular mechanisms of pathogenesis in Neisseria. The editors have assembled a team of highly regarded scientists, over 40 contributors, to describe the latest, up-to-date research, theory and clinical significance of molecular mechanisms in meningococcal disease. Leading authorities have contributed chapters on topics such as gene expression, genomics, biofilms, denitrification, adhesion strategies and mechanisms of cellular invasion. A section on the host response to neisserial infection covers inate immunity, complement, apoptosis, and acquired immunity while a section devoted to clinical correlation deals with vaccine development, epidemiology and antibiotic resistance.

The volume is highly recommended for microbiologists, epidemiologists and clinicians involved with Neisseria research or meningococcal disease and is a recommended text for all microbiology libraries.


"This book represents a comprehensive update on the current understanding of the molecular mechanisms of pathogenesis both in Neisseria meningitidis and Neisseria gonorrhoeae. The understanding of the gene expression strategies of pathogenic Neisseria is still limited but the recently published genome sequences of both the above mentioned species will provide invaluable insights into the basis of pathogenesis as well as on the study of new therapeutic interventions and preventive tools. Mechanisms of adhesion, cellular invasion, interference with the apoptotic cellular machinery and of antibiotic resistance are illustrated such as the role of the innate and acquired immunity in Neisseria infections. A comprehensive chapter is dedicated to the epidemiology of the diseases caused by the two species. Further, the most recent approaches for a future prevention these diseases by a universal neisserial vaccine are commented." from Society for Microbial Ecology and Disease

"written by outstanding and internationally highly recognized experts in the Neisseria research field ... The chapters are of the highest scientific quality including links to central primary publications on the different topics ... an excellent monography for the specialist" from Arzneimittelforschung/Drug Research (2010) 60: 226-227

"focuses effectively on (the) molecular approach to neisserial pathogenicity ... authoritative reviews of gene regulation, anaerobic survival, genome plasticity, epidemiology, vaccine development and the development of antibiotic resistance ... well-referenced" from Microbiology Today

"an excellent, comprehensive and updated review ... The volume is valuable and timely ... excellent, comprehensive, important, updated, well-written ... an impressive group of well-recognized experts that provide exceedingly interesting, comprehensive and up-to-date understanding ... valuable, timely and can be highly recommended for researchers, microbiologists, molecular biologists, epidemiologists, clinicians, vaccine manufacturers and students, who are involved and/ or interested in any topic involving pathogenic Neisseria species." from Expert Rev. Anti Infect. Ther. (2010) 8: 871-875.

Table of contents
Section I. Genetic Mechanisms
1. Gene Expression Strategies of the Pathogenic Neisseria
J.R. Mellin and Stuart Hill
The pathogenic Neisseria consists of the species Neisseria gonorrhoeae and Neisseria meningitidis, both of which are Gram-negative diplococci and exclusive human pathogens. Neisseria gonorrhoeae is the causative agent of gonorrhoeae and is transmitted via sexual contact and principally infects the mucosal surfaces of the cervix in women and the urethra in men. In contrast, N. meningitidis is transmitted via respiratory droplets leading to colonization of the nasopharynx, and in rare cases, dissemination of meningococci into the bloodstream and cerebrospinal fluid leading to meningitis and/or septicemia. In order to effectively colonize their respective niches within the human host, both N. gonorrhoeae and N. meningitidis must successfully compete with significant resident flora for space and nutrients, as well as evade host immune defenses. Consequently, this requires an ability to quickly sense and respond to a plethora of changing environmental stimuli. At the most fundamental level, this requires the modulation of gene expression as circumstances require. The following is a discussion of mechanisms of bacterial gene regulation with a specific focus on the strategies utilized by the pathogenic Neisseria to control gene expression of factors with roles in Neisserial pathogenesis. Topics will include the use of alternative sigma factors, positive and negative regulation of gene transcription by specific transcription factors and adaptation via the accumulation of temporally random spontaneous mutations within chromosomal DNA. Additionally, some discussion will focus on emerging mechanisms of gene regulation such as posttranscriptional regulation via small RNA molecules.
2. Regulation and Function of the Neisserial Denitrification Pathway: Life with Limited Oxygen
Virginia L. Clark, Vincent M. Isabella, Kenneth Barth and Tim W. Overton
Neisseria gonorrhoeae and N. meningitidis can grow anaerobically and/or microaerobically by anaerobic respiration, using the central two enzymes of the denitrification pathway. Nitrite reductase (AniA) converts nitrite to nitric oxide (NO), which is then reduced to nitrous oxide by nitric oxide reductase (NorB). The regulation of expression of aniA and norB is complex, involving multiple transcriptional activators and/or repressors. Transcription of aniA only occurs when oxygen concentrations are low due to the absolute requirement for FNR, an oxygen-sensitive transcriptional activator. When nitrite is present, it is converted to nitric oxide by AniA, resulting in inactivation of the repressor, NsrR, and commensurate derepression and NarP-dependent activation. Expression of norB is controlled by three repressors, NsrR, Fur, and ArsR. Transcription of norB can occur aerobically if nitric oxide is present, by inactivation of NsrR. Fur and ArsR compete for overlapping binding sites; Fur + iron displaces ArsR, causing further derepression of norB. In addition to enabling growth under oxygen-limited conditions, the denitrification pathway may alter nitric oxide concentrations during infection, leading to changes in NF-κB activation and resulting in suppression of the immune response. When a long-half life NO donor is added to mimic host production of NO, gonococci reduce NO from a pro-inflammatory (> 1 μM) to an anti-inflammatory steady state concentration (100-200 nM). In the presence of nitrite, most strains produce a high steady state level of NO, while strains requiring arginine, hypoxanthine, and uracil (AHU) set a steady state level < 1 μM. In meningococci the presence of the denitrification pathway protects the bacterium against the toxic effects of reactive nitrogen species and also alters cytokine production profiles by host macrophages.
3. Genomics and Recombination
John K. Davies
Analyses of the available genome sequences of Neisseria species and strains have considerably increased our knowledge of the recombination processes occurring within this genus. The accumulation of multiple copies of mobile genetic elements such as insertion sequences and bacteriophages has obviously contributed to genomic diversity. However these elements have also served as substrates for homologous recombination reactions that, at a low frequency, have resulted in various genomic rearrangements. Numerous examples of the horizontal acquisition of DNA segments are also obvious. The largest of these acquired DNA segments have been termed Islands of Horizontal Transfer, and appear to have been acquired at a low frequency via an as yet unknown process. A second class of horizontally acquired DNA segments, involving smaller fragments termed Minimal Mobile Elements, seem to be moving through the bacterial population at a higher frequency. These elements consist of a series of mutually exclusive cassettes, containing just a few genes, which target specific positions on the genomes. It is unclear how these elements evolved, but their movement appears to be facilitated by the natural transformation system, and integration occurs through homologous recombination involving conserved flanking genes. Each sequenced genome also contains a remarkable amount of non-coding repetitive DNA sequences. The most common of these repeats is involved in recognition and uptake of genus-specific DNA during transformation. Other repeats appear to be the target for site-specific recombinases or, especially when occurring in repeat arrays, the homologous recombination system. Finally, the genome sequences have also revealed numerous, previously unknown, examples of genes that appear to be subject to phase or antigenic variation. While the systems operating on a few of these genes have been known for some time, the magnitude of the variable gene repertoire was much greater than expected.
Section II. Interactions with Host Cells
4. Gonococcal Biofilms
Michael Apicella, Megan L. Falsetta, Ryan Neil and Christopher Steichen
Neisseria gonorrhoeae is an exclusive human pathogen. Our studies have demonstrated that it utilizes two distinct mechanisms for entry into human urethral and cervical epithelial cells involving different bacterial surface ligands and host receptors. Our recent studies have demonstrated that the gonococcus can form biofilms on glass surfaces and over human cells. In this chapter, we provided details of evidence for formation of gonococcal biofilms on human cervical epithelial cells during natural disease and provide further evidence that outer membrane blebbing by the gonococcus is crucial in biofilm formation over human cervical epithelial cells.
5. Newly Described Surface Structures and Adhesion Strategies of the Pathogenic Neisseria
Rosanna Leuzzi, Laura Serino, Davide Serruto and Mariagrazia Pizza
N. meningitidis and N. gonorrhoeae have evolved numerous surface-exposed proteins that mediate interaction with the host. Host?pathogen interaction is a multifactorial process and several surface structures have been shown to play a role in this process, suggesting that interactions mediated by different molecules are important in determining tissue tropism and invasive versus carriage potentials. Porins, type IV pili and opacity proteins are the major objects of investigation of neisserial pathogenesis and recent studies have improved our understanding of their functionality at a molecular level of detail. In the last few years, availability of neisserial genome sequences has enabled the identification of new surface proteins with a potential role as adhesins and virulence factors. Characterization of these new proteins have extended our knowledge on the multiple strategies evolved by pathogenic Neisseriae to infect the host.
6. Mechanisms of Cellular Invasion of Neisseria meningitidis
Etienne Carbonnelle, Xavier Nassif and Sandrine Bourdoulous
Neisseria meningitidis is an extracellular human specific pathogen responsible for septicemia and meningitis. Like most bacterial pathogens, N. meningitidis exploits host cell signaling pathways in order to promote its uptake by host cells. N.meningitidis does not have a type III nor a type IV secretion system. The signaling leading to bacterial internatilisation is induced by the type IV pili which are the main attribute mediating bacterial adhesion onto cells. The signaling induced following Type IV pilus mediated adhesion is responsible for the formation of microvilli like structures at the site of the bacterial-cell interaction. These mircovilli trigger the internalization of the bacteria inside the cells. A major consequence of these signaling events is a reorganization of the actin cytoskeleton leading to the formation of membrane protrusion engulfing bacterial pathogens into intracellular vacuoles. Efficient internalization of N. meningitidis also requires the activation of an alternative signaling pathway coupled to the activation of the tyrosine kinase receptor ErbB2. Beside Type IV pili other outer membrane proteins may be involved in other mechanism of bacteria internalization inside cells.
Section III. Host Response
7. Innate Immune Recognition of Neisseria meningitidis and Neisseria gonorrhoeae
Daniel C. Stein, Julia B. Patrone and Samuel Bish
The existing paradigm in neisserial infections is that these pathogens present a diverse, varying cell surface, and that one of the functions of this variability is that it allows them to avoid the killing actions of the hosts' innate immune system. In this chapter, we will define the important features of the innate immune system as it relates to neisserial disease, review the role of the variable cell surface antigens of N. gonorrhoeae and N. meningitidis in eliciting responses from various host cells, and provide some insights into the molecular basis of disease. We will describe what features are essential on the bacterium for initiating colonization in various anatomical locations and in the different sexes, and review how the host responds to these colonization events (disease vs asymptomatic colonization). We will also review the molecular mechanisms by which cells of the innate immune system become activated, and how different activation mechanisms can lead to different disease outcomes.
8. Interactions of Neisseria with Complement
Lisa A. Lewis, E. Burrowes, Peter A Rice and Sanjay Ram
Neisseria gonorrhoeae and Neisseria meningitidis have evolved intricate mechanisms to evade killing by the complement system. Binding of complement inhibitors, LOS sialylation and expression of capsular polysaccharide in the case of N. meningitidis all play key roles in enabling these bacteria to evade complement. The multiplicity of complement evasion strategies reflects the importance of overcoming this immune barrier. Neisserial resistance to complement mediated killing appears to be restricted to humans and may provide an explanation for the host specificity of neisserial disease. Recent advances in our understanding of neisserial complement evasion strategies should aid in developing better animal models and vaccine design.
9. Consequences of Pathogenic Neisseria Infection on Cellular Apoptosis
Sarah A. Follows and Paola Massari
A number of pathogens, including viruses, bacteria, and parasites, have evolved mechanisms to subvert apoptosis by either positively or negatively modulating host defenses. In particular, the inhibition of the apoptotic process by microbial pathogens has previously demonstrated importance in securing intracellular niches, which may be an important mechanism for microbial survival, replication or immune evasion. Similarly, the induction of apoptosis may be beneficial to pathogens by promoting escape from host cells or diminishing their effector functions, again promoting immune evasion. Conflicting studies have reported that infection with the facultative intracellular pathogens Neisseria gonorrhoeae and Neisseria meningitidis can either inhibit or induce apoptosis. Reports on Neisserial influence on the apoptotic response of host cells have been published consistently for almost ten years and will be the focus of this chapter. Overall, it seems that Neisseria species more often inhibit apoptosis, and this inhibition may allow time for adaptation to a new environment, intracellular replication, or immune evasion presumably leading to the spread of infection.
10. Role of Acquired Immunity in Neisseria Infections
Manish Sadarangani, Matthew D. Snape, Dominic F. Kelly, Gunnstein Norheim, J. Claire Hoe, Susan Lewis, Lee Wetzler and Andrew J. Pollard
A description of the clinical features of meningococcal disease first appears in the literature in 1805 in a thesis on an outbreak in Geneva, yet the global distribution of the organism and the diversity of its surface structures indicate a far longer history of association with man (perhaps as an acapsulate commensal), with diversity likely driven by immune-selection. Carriage studies indicate that almost all humans are likely to be exposed to Neisseria meningitidis at some stage and yet most do not develop disease. In early childhood, after loss of maternal antibody and before acquisition of adaptive immunity, the innate immune system effectively controls the meningococcus in most exposed individuals and prevents onset of invasive disease. However, the lower rates of disease in later childhood and amongst adults who have acquired specific antibody to the meningococcal surface indicates that the adaptive immune system is better still at preventing invasion into the bloodstream. In the first portion of this chapter we will consider both the natural acquisition of adaptive immunity to the meningococcus and the active induction of specific antibody through immunisation. There will also be a discussion regarding gonococcal acquired immunity at the end of this chapter.
Section IV. Clinical Correlations
11. Difficulty in Developing a Neisserial Vaccine
Kate L. Seib and Rino Rappuoli
Diseases caused by Neisseria meningitidis and Neisseria gonorrhoeae, are a significant health problem worldwide, the control of which are largely dependent on the availability and widespread use of comprehensive meningococcal and gonococcal vaccines. Unfortunately, the development of Neisserial vaccines has been challenging due to the nature of these organisms, in particular the heterogeneity, variability and/or poor immunogenicity of their outer surface components. As strictly human pathogens, they are highly adapted to the host environment but have evolved several mechanisms to remain adaptable to changing microenvironments and avoid elimination by the host immune system. Currently, serogroup A, C, Y and W-135 meningococcal infections can be prevented by vaccines. However there is no comprehensive serogroup B vaccine, and the prospect of developing a gonococcal vaccine is remote.
12. Epidemiology in the Vaccine Era
Caroline Trotter, Gwenda Hughes and Cathy Ison
The pathogenic species of the genus Neisseria, Neisseria meningitidis and Neisseria gonorrhoeae share much of their genome, but differ markedly in many other respects. N. meningitidis colonises the mucosal surfaces primarily of the upper respiratory tract as part of the normal flora and occasionally invades to cause systemic disease with subsequent serious sequelae, morbidity and mortality, compared to N. gonorrhoeae which mainly colonises the mucosa of the anogenital tract, rarely invades to cause serious systemic disease but is always considered a pathogen. N. meningitidis and N. gonorrhoeae are inherently susceptible to antimicrobial agents but N. gonorrhoeae has been particularly adept at acquiring or developing resistance to many therapeutic agents, which has not been such a major problem in N. meningitidis. Many of the major antigens are shared between these two species with the exception of the polysaccharide capsule found on the meningococcus, which can elicit a protective immune response. There is a lack of an apparent protective immune response to N. gonorrhoeae, with multiple episodes occurring in a single individual which results from the extra-ordinary ability of the organism for antigenic variation, in addition to the absence of the capsule. This chapter addresses the epidemiology of both of these neisserial infections and consequently allows the comparison of an infection with the potential to be controlled by vaccination with a second which is largely controlled by antimicrobial therapy alone. This is all the more interesting given that genetically these organisms are so closely related and came from the same progenitor
13. Molecular Mechanisms of Antibiotic Resistance Expressed by the Pathogenic Neisseria
William M. Shafer, Jason P. Folster and Robert A. Nicholas
Diseases caused by the pathogenic Neisseria (N. gonorrhoeae and N. meningitidis) have been successfully treated with antibiotics for the past 70 years. However, a disturbing trend worldwide is the increasing prevalence of strains with resistance to inexpensive and widely available antibiotics (e.g., penicillin, tetracycline and ciprofloxacin) and the emergence of strains exhibiting decreased susceptibility to effective antibiotics that are expensive and not always available (e.g. third-generation cephalosporins and the newer macrolides). Given the global nature of gonococcal and meningococcal diseases, the worldwide distribution of antibiotics, differing social practices in controlling and monitoring antibiotic availability, and geographical differences in treatment regimens, it is likely that the global problem of antibiotic resistance will continue (and worsen) in the foreseeable future. By understanding the mechanisms of antibiotic resistance in gonococci and meningococci, resistance to antibiotics currently in clinical practice can be anticipated and the design of novel antimicrobials to circumvent this problem can be undertaken more rationally. Herein, we review the genetic and physiologic basis by which the pathogenic Neisseria developed resistance to historically important antibiotics and how resistance to newer antibiotics is emerging.

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(EAN: 9781904455516 9781912530953 Subjects: [bacteriology] [microbiology] [medical microbiology] [molecular microbiology] )