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Pathogens and Disease May 2022Chlamydia trachomatis is a bacterial obligate intracellular parasite and a significant cause of human disease, including sexually transmitted infections and trachoma....
Chlamydia trachomatis is a bacterial obligate intracellular parasite and a significant cause of human disease, including sexually transmitted infections and trachoma. The bacterial RNA polymerase-binding protein DksA is a transcription factor integral to the multicomponent bacterial stress response pathway known as the stringent response. The genome of C. trachomatis encodes a DksA ortholog (DksACt) that is maximally expressed at 15-20 h post infection, a time frame correlating with the onset of transition between the replicative reticulate body (RB) and infectious elementary body (EB) forms of the pathogen. Ectopic overexpression of DksACt in C. trachomatis prior to RB-EB transitions during infection of HeLa cells resulted in a 39.3% reduction in overall replication (yield) and a 49.6% reduction in recovered EBs. While the overall domain organization of DksACt is similar to the DksA ortholog of Escherichia coli (DksAEc), DksACt did not functionally complement DksAEc. Transcription of dksACt is regulated by tandem promoters, one of which also controls expression of nrdR, encoding a negative regulator of deoxyribonucleotide biosynthesis. The phenotype resulting from ectopic expression of DksACt and the correlation between dksACt and nrdR expression is consistent with a role for DksACt in the C. trachomatis developmental cycle.
Topics: Bacterial Proteins; Chlamydia Infections; Chlamydia trachomatis; Escherichia coli; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; HeLa Cells; Humans
PubMed: 35388904
DOI: 10.1093/femspd/ftac007 -
Current Topics in Microbiology and... 2018Chlamydial infections lead to a number of clinically relevant diseases and induce significant morbidity in human populations. It is generally understood that certain... (Review)
Review
Chlamydial infections lead to a number of clinically relevant diseases and induce significant morbidity in human populations. It is generally understood that certain components of the host immune response to infection also mediate such disease pathologies. A clear understanding of pathogenic mechanisms will enable us to devise better preventive and/or intervention strategies to mitigate the morbidity caused by these infections. Over the years, numerous studies have been conducted to explore the immunopathogenic mechanisms of Chlamydia-induced diseases of the eye, reproductive tract, respiratory tract, and cardiovascular systems. In this article, we provide an overview of the diseases caused by Chlamydia, animal models used to study disease pathology, and a historical context to the efforts to understand chlamydial pathogenesis. Furthermore, we discuss recent findings regarding pathogenesis, with an emphasis on the role of the adaptive immune response in the development of chlamydial disease sequelae. Finally, we summarize the key insights obtained from studies of chlamydial pathogenesis and avenues that remain to be explored in order to inform the next steps of vaccine development against chlamydial infections.
Topics: Adaptive Immunity; Animals; Chlamydia Infections; Chlamydia trachomatis; Disease Models, Animal; Humans
PubMed: 27370346
DOI: 10.1007/82_2016_18 -
Bulletin of Mathematical Biology Feb 2021Chlamydia trachomatis is an important bacterial pathogen that has an unusual developmental switch from a dividing form (reticulate body or RB) to an infectious form...
Chlamydia trachomatis is an important bacterial pathogen that has an unusual developmental switch from a dividing form (reticulate body or RB) to an infectious form (elementary body or EB). RBs replicate by binary fission within an infected host cell, but there is a delay before RBs convert into EBs for spread to a new host cell. We developed stochastic optimal control models of the Chlamydia developmental cycle to examine factors that control the number of EBs produced. These factors included the probability and timing of conversion, and the duration of the developmental cycle before the host cell lyses. Our mathematical analysis shows that the observed delay in RB-to-EB conversion is important for maximizing EB production by the end of the intracellular infection.
Topics: Chlamydia Infections; Chlamydia trachomatis; Host Microbial Interactions; Humans; Models, Biological
PubMed: 33594486
DOI: 10.1007/s11538-020-00846-4 -
Frontiers in Cellular and Infection... 2022The obligate intracellular bacteria store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the...
The obligate intracellular bacteria store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the bacteria can take up only glucose-6-phosphate (Glc6P). We tested whether the conversion of Glc1P into Glc6P could be catalyzed by a phosphoglucomutase (PGM) of host or bacterial origin. We found no evidence for the presence of the host PGM in the vacuole. Two proteins, CT295 and CT815, are potential PGMs. By reconstituting the reaction using purified proteins, and by complementing PGM deficient fibroblasts, we demonstrated that only CT295 displayed robust PGM activity. Intriguingly, we showed that glycogen accumulation in the lumen of the vacuole of a subset of species (, , ) correlated with the presence, in CT295 orthologs, of a secretion signal recognized by the type three secretion (T3S) machinery of . and do not accumulate glycogen, and their CT295 orthologs lack T3S signals. In conclusion, we established that the conversion of Glc1P into Glc6P was accomplished by a bacterial PGM, through the acquisition of a T3S signal in a "housekeeping" protein. Acquisition of this signal likely contributed to shaping glycogen metabolism within .
Topics: Chlamydia trachomatis; Glucose-6-Phosphate; Glycogen; Phosphoglucomutase; Vacuoles
PubMed: 35795184
DOI: 10.3389/fcimb.2022.866729 -
Advances in Clinical and Experimental... 2012Chlamydiae are microorganisms exhibiting characteristics intermediate between bacteria and viruses. Chlamydia is widespread in the natural world, intracellular parasites... (Review)
Review
Chlamydiae are microorganisms exhibiting characteristics intermediate between bacteria and viruses. Chlamydia is widespread in the natural world, intracellular parasites of people and animals. They are capable of independent reproduction, because they do not synthesize ATP, in its development cycle using the host cell metabolic pathways. The life cycle of these microorganisms is original, unique among bacteria and lasts from 24 to 48 hours. Chlamydia antigens consist of 4 groups: group-specific, species-specific, type-specific and subspecies-specific. The group of species-specific antigens consists of MOMP and heat shock proteins. C. trachomatis is a potent immunogen, stimulating the immune processes of microorganisms. In the course of C. trachomatis infection, the response mechanisms involved are: non-specific, specific, humoral and cellular. Chronic infection is characterized by maintenance of microorganisms in the host cell. Inflammation is formed in less time and with increased intensity and has a rapid immune response on the part of previously sensitized lymphocytes. C. trachomatis infections are the most common bacterial sexually-transmitted infections. It represents an important clinical problem for doctors in many areas of medicine such as dermatology, venereology, ophthalmology, gynecology and obstetrics, rheumatology and others. Chlamydial infections are important pathogens in medical practice, not only because they cause disease in various fields of medicine, but also because of the large proportion of the population suffering and exposed to these microbial infections. Chlamydial infections are characterized by multifocality and polymorphism changes. Chlamydia causes inflammation in the adult urethra and cervix with the possibility of serious complications, and can cause perinatal infections in infants.
Topics: Animals; Antigens, Bacterial; Chlamydia Infections; Chlamydia trachomatis; Epithelial Cells; Humans; Species Specificity
PubMed: 23457138
DOI: No ID Found -
Indian Journal of Medical Microbiology 2017Urogenital infection due to Chlamydia trachomatis (CT) is one of the most common bacterial sexually transmitted infections (STIs) and is a major public health problem... (Review)
Review
Urogenital infection due to Chlamydia trachomatis (CT) is one of the most common bacterial sexually transmitted infections (STIs) and is a major public health problem worldwide. Molecular characterisation of CT is important for understanding the pathophysiological mechanisms of chlamydial disease and its transmission dynamics in sexual networks. Traditionally, strain typing of CT was based on serotyping methods characterising the major outer membrane protein (MOMP). With the advent of polymerase chain reaction and sequencing the era of molecular typing began. Molecular characterization of CT strains is based on sequence analysis of ompA gene encoding MOMP. However, in due course of time, improvements were made to enhance the discriminatory power of sequencing and quality of epidemiological information. New high-resolution genotyping methods using multiple loci such as multilocus sequence typing (MLST) and multiple loci variable number of tandem repeats (MLVA) were developed but were unable to differentiate mixed infections (MIs). The development of DNA-hybridisation methods emerged as a major breakthrough in detecting MIs. Although MLST and MLVA are more discriminative than other genotyping methods, they are laborious and expensive. DNA microarray technique is an affordable alternative for genotyping. Since recombination is widespread in the CT genome, ompA is not a reliable marker for phylogenetic studies; hence, whole genome sequencing may provide maximum phylogenetic resolution of CT strains. A descriptive review is provided of the various molecular CT typing methods. The vital information gained can be used for formulating screening programmes, targeted prevention and optimising therapeutic measures aiming to reduce disease transmission.
Topics: Chlamydia Infections; Chlamydia trachomatis; Genotype; Genotyping Techniques; Humans; Molecular Epidemiology; Molecular Typing; Reproductive Tract Infections
PubMed: 28303813
DOI: 10.4103/ijmm.IJMM_16_341 -
Current Protocols in Microbiology May 2017Gene inactivation is essential for forward and reverse genetic approaches to establish protein function. Techniques such as insertion or chemical mutagenesis have been...
Gene inactivation is essential for forward and reverse genetic approaches to establish protein function. Techniques such as insertion or chemical mutagenesis have been developed to mutagenize chlamydiae via targeted or random mutagenesis, respectively. Both of these approaches require transformation of chlamydiae to either introduce insertion elements or complement mutants. We have recently developed a targeted mutagenesis strategy, fluorescence-reported allelic exchange mutagenesis (FRAEM), to delete Chlamydia trachomatis L2 genes. This approach overcomes several barriers for genetically manipulating intracellular bacteria. Perhaps most significantly, FRAEM employs fluorescence reporting to indicate successful transformation and subsequent recombination events. Three protocols are provided that detail methods to construct gene-specific suicide vectors, transform C. trachomatis L2 to select for recombinants, and isolate clonal populations via limiting dilution. In aggregate, these protocols will allow investigators to engineer C. trachomatis L2 strains carrying complete deletions of desired gene(s). © 2017 by John Wiley & Sons, Inc.
Topics: Chlamydia trachomatis; Gene Knockout Techniques; Transformation, Bacterial
PubMed: 28510361
DOI: 10.1002/cpmc.31 -
Infection and Immunity Jul 2023Chlamydia trachomatis is an obligate intracellular pathogen that replicates in a host-derived vacuole termed the inclusion. Central to pathogenesis is a type III...
Chlamydia trachomatis is an obligate intracellular pathogen that replicates in a host-derived vacuole termed the inclusion. Central to pathogenesis is a type III secretion system that translocates effector proteins into the host cell, which are predicted to play major roles in host cell invasion, nutrient acquisition, and immune evasion. However, until recently, the genetic intractability of C. trachomatis hindered identification and characterization of these important virulence factors. Here, we sought to expand the repertoire of identified effector proteins and confirm they are secreted during C. trachomatis infection. Utilizing bioinformatics, we identified 18 candidate substrates that had not been previously assessed for secretion, of which we show four to be secreted, using Yersinia pseudotuberculosis as a surrogate host. Using adenylate cyclase (CyaA), BlaM, and glycogen synthase kinase (GSK) secretion assays, we identified nine novel substrates that were secreted in at least one assay. Interestingly, only three of the substrates, shown to be translocated by C. trachomatis, were similarly secreted by Y. pseudotuberculosis. Using large-scale screens to determine subcellular localization and identify effectors that perturb crucial host cell processes, we identified one novel substrate, CT392, that is toxic when heterologously expressed in Saccharomyces cerevisiae. Toxicity required both the N- and C-terminal regions of the protein. Additionally, we show that these newly described substrates traffic to distinct host cell compartments, including vesicles and the cytoplasm. Collectively, our study expands the known repertoire of C. trachomatis secreted factors and highlights the importance of testing for secretion in the native host using multiple secretion assays when possible.
Topics: Humans; Bacterial Proteins; Chlamydia trachomatis; HeLa Cells; Cytoplasm; Type III Secretion Systems; Chlamydia Infections
PubMed: 37347192
DOI: 10.1128/iai.00491-22 -
The Journal of Infectious Diseases Jun 2010An unanswered question concerning prevalence and disease severity of Chlamydia trachomatis genital infection is whether more prevalent strains or strains more likely to... (Review)
Review
An unanswered question concerning prevalence and disease severity of Chlamydia trachomatis genital infection is whether more prevalent strains or strains more likely to cause serious disease complications are causally associated with specific virulence attributes. The major method for distinguishing chlamydial strains is based on differences in the major outer membrane protein (MOMP). A subset of MOMP serovars (D and E serovars) are easily the most prevalent strains identified worldwide, but MOMP serovar and genovar analyses have not yielded consistent strain-dependent virulence distinctions. Expansion of the definitions of chlamydial strains beyond the MOMP paradigm are needed to better understand virulence properties for this pathogen and how these properties reflect disease severity. Substantive genetic and phenotypic differences have emerged for the 2 major C. trachomatis pathobiotypes associated with either trachoma or sexually transmitted diseases, but differences within the sexually transmitted disease group have not yielded reliable disease severity attributes. A number of candidate virulence factors have been identified, including the polymorphic outer membrane autotransporter family of proteins, the putative large cytotoxin, type III secretion effectors, stress response proteins, and proteins or other regulatory factors produced by the cryptic plasmid. Continued work on development of a chlamydial gene transfer system and application of genomic approaches to large collections of clinical isolates will be required to associate key chlamydial virulence factors with prevalence and disease severity in a definitive way.
Topics: Bacterial Proteins; Bacterial Toxins; Chlamydia Infections; Chlamydia trachomatis; Glycolipids; Humans; Lipopolysaccharides; Phenotype; Porins; Prevalence; Species Specificity; Stress, Physiological; Virulence Factors
PubMed: 20470049
DOI: 10.1086/652398 -
Clinical Microbiology Reviews Oct 2015Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen worldwide. Infection can result in serious reproductive pathologies, including pelvic... (Review)
Review
Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen worldwide. Infection can result in serious reproductive pathologies, including pelvic inflammatory disease, ectopic pregnancy, and infertility, in women. However, the processes that result in these reproductive pathologies have not been well defined. Here we review the evidence for the human disease burden of these chlamydial reproductive pathologies. We then review human-based evidence that links Chlamydia with reproductive pathologies in women. We present data supporting the idea that host, immunological, epidemiological, and pathogen factors may all contribute to the development of infertility. Specifically, we review the existing evidence that host and pathogen genotypes, host hormone status, age of sexual debut, sexual behavior, coinfections, and repeat infections are all likely to be contributory factors in development of infertility. Pathogen factors such as infectious burden, treatment failure, and tissue tropisms or ascension capacity are also potential contributory factors. We present four possible processes of pathology development and how these processes are supported by the published data. We highlight the limitations of the evidence and propose future studies that could improve our understanding of how chlamydial infertility in women occurs and possible future interventions to reduce this disease burden.
Topics: Chlamydia Infections; Chlamydia trachomatis; Female; Humans; Infertility; Pregnancy; Risk Factors
PubMed: 26310245
DOI: 10.1128/CMR.00035-15