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Category: Microbial Genetics and Molecular Biology; Bacterial Pathogenesis
This important and timely volume is the first complete review of chlamydial research in ten years. In that time there have been substantial research advances, and the entry of many researchers into the field heralds a new era. The expansion of the field, fueled by the identification of a new emerging chlamydial pathogen, Chlamydia pneumoniae, and the completion of genome sequences for C. trachomatis and C. pneumoniae, provides the impetus for a complete review of chlamydial research.
This new volume identifies the major issues and questions that will lead to future chlamydial research. It illustrates how genomics is changing the chlamydial research agenda and explores the role of cell biology and the immune response in pathogenesis and immunity.
Designed as a synthetic, comparative volume, this book comprehensively compares, contrasts, and integrates issues across all chlamydial species. The contributors provide a thorough review of previous research and indicate the top research needs in each area.
Electronic Only, 346 pages, illustrations, index.
Chlamydia spp. cause a variety of human and animal diseases and are one of the most prevalent causes of sexually transmitted diseases. By 16S rRNA analysis, chlamydiae fall into one of about 40 "divisions," or main relatedness groups, that make up the bacterial phylogenetic domain. The application of PCR coupled with rRNA-based phylogenetic techniques has resulted in a substantial accumulation of Chlamydia-related sequences. Phylogenetic analyses from several laboratories generally concur in their assessments of the phylogeny of the group. The Chlamydia species are all relatively closely related, yet until recently they have represented an entire bacterial division. Phylogenetic analyses carried out with the RNase P RNA sequences from C. trachomatis, C. pneumoniae, and C. psittaci, the only ones available, support the rRNA tree, showing that C. pneumoniae and C. psittaci are more closely related to each other than either is to C. trachomatis. All known members of the Chlamydiales phylogenetic division are intracellular parasites, although it is possible that free-living instances of the division exist in the environment. Members of the Planctomycetales and Verrucomicrobiales divisions are little-studied organisms that recent molecular studies show to be conspicuous in the environment. Although their relatedness through sequence comparisons is currently ambiguous, an additional similarity between members of these groups and members of Chlamydiales is the apparent lack of peptidoglycan in their cell walls. Complete genome sequences of representatives of the Planctomycetales and Verrucomicrobiales will facilitate a better analysis of their possible specific relationships with the Chlamydiales, and increase knowledge of bacterial division-level diversity.
The genome sequences of Chlamydia trachomatis and C. pneumoniae contain the respective autobiographies that have been translated, read, and begun to be interpreted. The C. trachomatis species contains three biovariants: trachoma, lymphogranuloma venereum (LGV), and murine (MoPn). Strains of C. trachomatis that are natural pathogens of humans are members of either the trachoma or LGV biovar. Chlamydiae have substantial capacity for DNA repair and recombination, including mismatch repair (MutL, MutS, and three parologous MutY proteins), the excinuclease UvrABCD complex, transcription-repair coupling factor (TRCF), and a number of proteins implicated in recombination-coupled repair such as RecA, RecBCD, and RecJ. One of the phenotypic hallmarks of chlamydial development is the remarkably condensed nucleoid structure observed in elementary bodies (EB). The central metabolism determined for C. trachomatis and C. pneumoniae was found to be conserved. It appears that chlamydiae use fewer transport systems than free-living bacteria and rely on transport systems with broad specificity. The presence of an apparently complete glycolytic pathway was complemented by a tricarboxylic acid (TCA) cycle. The C. trachomatis genome contains genes encoding TrpA, TrpB, and TrpC, as well as a gene encoding a regulator of tryptophan gene transcription, TrpR. In the context of the unique biology and phylogeny of chlamydiae, the current challenges for productive microbiological research, and the medical imperative for progress in understanding chlamydial infection and disease, is that having a database available for the entire C. trachomatis and C. pneumoniae genomes will provide enduring benefits for chlamydial research.
This chapter summarizes what is known about the structural and biochemical differences between elementary body (EB) and reticulate body (RB) and the mechanisms by which genes are regulated during the developmental cycle. The EB is adapted for extracellular survival, which for some strains of Chlamydia psittaci and C. pecorum may extend to prolonged exposure outside of the host organism. This chapter discusses stage-specific structures and biochemical events. Several homologs of proteins that regulate alternative sigma factor activities in bacteria (AtoS, RsbW, two RsbV orthologs, and RsbU) are encoded by the chlamydial genome. Mathews and Sriprakash were the first to carry out mutational analysis of a chlamydial promoter. The gene analyzed encodes two short transcripts with the same 5' end but different 3' ends; the transcripts generated are antisense to a predicted integrase gene encoded by the plasmid of C. trachomatis. One of the most interesting observations was that deletion of the N-terminal and C-terminal extension sequences of σ66 ablated transcription from P2, relating structural differences between σ66 and σ70 to differences in promoter recognition for the first time. The purpose of the multiple transcripts from genes/operons remains a mystery, and further investigation may show that multiple transcripts are the exception rather than the rule. The complete sequencing of the chlamydial genome will provide signposts for research in the future and will reduce much of the arduous gene sequencing that was so much a part of chlamydial research in the past.
This chapter deciphers chlamydiae's metabolic capabilities from the complete genome sequence. On the basis of their primary function in growth, metabolic reactions have been categorized as assembly reactions, polymerization reactions, biosynthetic reactions, and fueling reactions. Numerous in situ studies have suggested that chlamydiae show strain-to-strain variation in amino acid requirements and that they compete with the host for the available amino acid pool. All cells have an absolute requirement for cofactors. Nevertheless, it is not unusual for small-genome organisms to lack the ability to synthesize cofactors. Genome sequence information indicates that chlamydiae are capable of limited cofactor biosynthesis. Fatty acid biosynthesis, a series of reactions that requires a lot of energy, is a metabolic process that is absent from minimal-genome organisms that have been sequenced. As a result the fatty acid composition of these organisms to a large extent reflects that present in the growth medium. Nucleotides are found in significant amounts only inside of cells, because they are rapidly degraded in the extracellular environment. Numerous studies on nucleotide metabolism using both host-free reticulate bodies (RBs) and an in situ approach employing as host wild-type and various mutant cell lines, with welldefined genetic deficiencies in nucleotide metabolism, have been carried out. These studies conclude that chlamydiae cannot synthesize nucleotides de novo or salvage nucleotides. This chapter describes Embden-Meyerhoff-Parnas (EMP) pathway, the pentose phosphate pathway (PPP), gluconeogenesis, respiration, and ATPase complex.
Chlamydiae are extremely successful pathogens of humans and animals. The chlamydial developmental cycle may be considered superficially analogous to bacterial sporulation in that it consists of an environmentally stable cell type, called the elementary body (EB), and a functionally and morphologically distinct vegetative cell type, termed the reticulate body (RB). Electrostatic interactions play an important role in at least the initial stages of infection. Attachment is dependent upon cations to neutralize the net negative surface charge of both host and parasite. Several chlamydial components have been proposed at one time or another to function as adhesins. A number of EB surface components have been proposed as potential ligands mediating attachment to host cells. Currently, heparan sulfate-like proteoglycans are considered one of the more promising candidates mediating at least an initial electrostatic interaction between the EB and the host cell surface. The general implication is that chlamydiae, like many other intracellular pathogens, similarly stimulate signal transduction pathways, including tyrosine phosphorylation of host proteins involved in rearrangements of the actin skeleton to promote entry. This chapter talks about intracellular development. Intracellular parasites have evolved diverse strategies for evasion of host cellular defense mechanisms associated with adaptations for survival in distinct intracellular compartments. The chapter discusses effects of the host cell. It is essential that chlamydiae maintain the integrity of the host cell for the duration of their intracellular growth because they are obligate intracellular parasites.
Chlamydiae cause a wide variety of diseases. In their natural hosts, chlamydial infections usually cause relatively mild diseases characterized by persistent infections with relatively poor immunity, so that recurrent infections can occur. C. psittaci is an extraordinarily common organism among avian species. While infections in the wild may affect only a small fraction of the birds at any given time, the agents are highly infectious and often cause enteric and respiratory infection. The chapter first talks about C. psittaci infections. Many cases of human psittacosis go undiagnosed because it requires a high index of suspicion on the part of a clinician to test cases of atypical pneumonia or unusual febrile diseases for psittacosis. Control of psittacosis depends on control of the avian sources of infection. Despite the wide host range of C. psittaci, infection of humans from nonavian animals is rare. Next, the chapter discusses C. trachomatis infection. C. trachomatis is passed from eye to eye by direct contact. The epidemiology of trachoma continues to provide hope for those trying to produce an effective vaccine for trachoma. Finally, the chapter focuses on C. pneumoniae infections. C. pneumoniae is recognized as an important cause of respiratory disease in young adults and may cause serious respiratory disease in older debilitated individuals. There are no gold standards for diagnosis of C. pneumoniae infection. Tetracycline and erythromycin are effective against C. pneumoniae in vitro. C. pneumoniae has also been associated with a bewildering array of chronic diseases.
This chapter discusses the possible role of gamma interferon (IFN-γ) and heat shock proteins (Hsps) in the pathogenesis of chlamydial disease. It reviews preliminary evidence from trachoma and pelvic inflammatory disease (PID) suggesting that human genotype exerts a substantial influence. It discusses some of the evidence behind current concepts of chlamydial disease mechanisms, and focuses on vitro studies that provide clues as to the potential of chlamydiae to cause enduring, inapparent infection and then examines the clinical evidence from human infection. It describes the role of cytokines in chlamydial infection. Chlamydia-induced expression of cytokines by conjunctival epithelial cells has been observed in biopsies from subjects with trachoma. The chapter then focuses on the role of chlamydial heat shock proteins in the pathogenesis of disease. The most significant advance in the clinical aspects of chlamydial research in the last decade has been the recognition that C. pneumoniae is associated with chronic human disease. The issues surrounding the possible association of C. pneumoniae infection with coronary artery disease (CAD) and the possible mechanisms by which C. pneumoniae might cause heart disease are summarized to illustrate the problems involved in proving that chlamydiae have a significant etiologic role in chronic human disease. The case for a causal role of C. pneumoniae in CAD is greatly strengthened if plausible molecular and cellular mechanisms involving known risk factors can be demonstrated. There is a need for further studies at the cellular and molecular levels on the mechanisms of chlamydia-induced disease.
This chapter addresses the question of and data for natural immunity to chlamydial infection, focusing on data on Chlamydia trachomatis infections in humans. It summarizes the limited information on immunity to human C. pneumoniae infection, and discusses the basis of individual susceptibility to chlamydial infection and disease with reference to chlamydial immunity. The relationships between determinants for host susceptibility to infection, persistence of infection, and propensity to cause disease are highlighted in this chapter. The chapter also discusses of the role that immune evasion mechanisms have on interventions such as vaccines. Chlamydiae are surprisingly susceptible to inactivation by humoral and cellular innate defenses. Results from several observations suggested that major outer membrane protein (MOMP)-specific TH1 CD4 T cells are important in immunity to C. trachomatis infection and disease and that Hsp60-specific TH2-like CD4 T cells are associated with the pathological sequelae of persistent chlamydial infection. The authors suggest that Fc-receptor-mediated cell entry enhanced susceptibility to chlamydial infection. A complex web of host and pathogen determinants appears to constrain the outcome of chlamydial infection. Infection with C. pneumoniae induces strong serum antibody responses. At the population level, serum antibodies are principally acquired between ages 5 and 14 years, with approximately 50 to 75% of adults having antibody to C. pneumoniae. Both peripheral blood and synovial fluid mononuclear cells have been successfully used in lymphoproliferation assays.
This chapter provides a thorough discussion of the naturally occurring immune response to chlamydial infection of the genital tract, respiratory tract, and conjunctiva, including the events leading to resolution of infection, the mechanisms involved in resolution, and the events and mechanisms participating in the immune response to reinfection. The chapter addresses the ongoing development of a chlamydial vaccine including a review of vaccine studies, potential immunogens, and strategies of immunization. Unquestionably, there is a strong immune response in humans resulting from genital, ocular, or respiratory infection with relevant species of Chlamydia. As with many infections, immunity is seldom an all-or-none matter; therefore, a section explores some of the potential parameters which contribute to the resistance or susceptibility to reinfection. In addition, since immunity, particularly in adolescents, appears to be short-lived, any vaccine that is developed must do better than the natural infection, which is something that has proven to be extremely difficult. The chapter further reviews attempts at immunization with different immunogens or forms of immunogens, as well as the effect of the immunization route. Finally, the chapter discusses the potential immunization strategies, based on one's knowledge of the immune response and disease pathogenesis. In evaluating possible vaccine strategies for chlamydial disease, it is important to remember that we are dealing with the prevention of different disease entities. It is unlikely that a single vaccination protocol will be effective against trachoma, genital disease, pneumonia, coronary artery disease, and veterinary diseases.
The ultimate goals of infectious disease research are to prevent infection, morbidity, and mortality. The spectrum of chronic diseases linked to chlamydial infection falls into two broad categories: (i) those for which the evidence for causality is considered conclusive and (ii) those for which the evidence is insufficient to be considered causal. Whether chronic chlamydial infections can be "cured" with appropriate antibiotic therapy is one of the critical research questions facing the medical community. Intensive preclinical and clinical investigations are under way to develop topical microbicides that will prevent chlamydial infection as well as other sexually transmitted infections, including HIV infection. Chronic chlamydial infection in the upper reproductive tract, or pelvic inflammatory disease (PID), is one of the most serious consequences of this sexually transmitted disease for women. There is an urgent need for rapid, inexpensive, easy-to-use diagnostic tests for chlamydial infection. Data from human and veterinary studies suggest that chlamydial infections probably play an important role in pregnancy outcomes. The potential for chlamydial species to precipitate spontaneous abortion is suggested by manifestations of C. psittaci infection in sheep. Psittacosis has long been recognized as a systemic disease. The infectious agent gains entry through a mucosal surface and disseminates widely. Recent studies of brain tissue from patients with late-onset Alzheimer's disease have resulted in startling findings. Investigators have identified chlamydial nucleic acid sequences in disease plaques from 17 of 19 patients with late-onset Alzheimer's disease; two of these tissue samples also contained viable elementary bodies.
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