Chlamydia: Intracellular Biology, Pathogenesis, and Immunity

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 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 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 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.

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.