Life cycle to Chlamydia pneumoniae 

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... 1990). Chlamydia species have similar morphology and a common development cycle. By adapting to the intracellular compartment, chlamydiae lost a lot of the energy producing metabolic ways and the ability to produce ATP, but preserved some major metabolic activities, such are: glycolysis, respiration, pentoses biosynthesis. Development of intracellular chlamydiae depends on ATP and other high energy compounds derived from the host cell. Chlamydiae possess the enzymatic systems required for DNA, RNA and proteins synthesis, but they use many of the host cell precursors (nucleotides, amino acids, nutrients, vitamins, various cofactors) (Madigan et al., 1997). In terms of structure, there were identified two chlamydia types: the infectious, nonreplicating elementary body (EB) and the noninfectious, but actively replicating reticulate body (RB), which are alternating in the development of the infectious cycle. The two morphologically distinct forms - the EBs and RBs - are representing adaptations to the extracellular environment and respectively to the intracellular one. The infectious particle, stable in the extracellular environment is a small cell, called the elementary body. They enter the host cell, multiply and disseminate in the extracellular environment. To complete these steps, chlamydiae undergo a developmental cycle that includes forms with alternating morphology and function. Chlamydia cell wall is similar to the Gram-negative bacteria, with increased lipid content, but does not contain peptidoglycan (Hatch, 1996) (Fig. 1). Pentapeptidic similar components may be present, because their growth and division is altered in the presence of β -lactam antibiotics. The outer membrane of Chlamydia pneumoniae is composed of lipopolysaccharides (LPS) and heat-shock proteins (HSP) that are genus specific (Matsumoto et al., 1991, Shirai et al., 2000). The bacterial family of Chlamydiaceae comprises a group of obligate intracellular pathogens which harbour a highly truncated LPS, being composed of KDO (2-keto-3-deoxyoctonate) units only. In all chlamydial species, the linear trisaccharide a-KDO-(2 - 8)-a-KDO-(2 - 4)-a- Kdo has been found, thereby constituting a family specific antigen. Antibodies raised against these neoglycoconjugates displayed a wide range of specificities and affinities. Several major outer membrane proteins (MOMP) identified are detectable by monoclonal antibodies and are species specific (Matsumoto et al., 1991, Shirai et al., 2000). Under these persistence-inducing conditions, the chlamydial Hsp60 appears to be highly upregulated. Chlamydial Hsp60 has proinflammatory effects by directly activating mononuclear leukocytes, which are mediating the inflammatory response. Chlamydial persistence is characterized by morphologically aberrant RBs that do not undergo cytokinesis, considered a third chlamydial type, called the noninfectious, nonreplicating persistent body (PB). Persistent Chlamydia , however, re-enter the productive life cycle upon removal of the stress factor. The infectious chlamydial form is the EB, which is adhering to the target cell membrane and initiates penetration. Elementary body is small, dense, with a rigid cell wall, given by the multiple SS bonds and to two other major outer membrane proteins (CRPs): a wall protein of 60 kDa and the outer membrane lipoprotein of 12 kDa. EB is resistant to environmental factors favouring survival in the extracellular environment after cell lysis and switching from one cell or one host to another. EB is not dividing, is metabolically inert, but has high affinity for epithelial cells. Its role is to spread the infection from one cell to another. Its membrane contains heparan-sulphate (proteoglycan), a ligand, through which they are attached to the microvilli and subsequently embedded in clatrin vesicles by receptors mediated endocytosis. Chlamydiae remain in the intracellular vacuole with non acid pH and avoid the fusion of the phagocytic vesicle with the lysosomes by unknown mechanisms. Inside the large vacuole, chlamydiae are redistributed from the cell periphery to the nucleus periphery by a mechanism dependent on actin F. The EB undergoes morphological changes and reorganization in the RB which is larger, metabolically active, and divides repeatedly by binary fission and becomes visible as a microcolony known as chlamydial inclusion. RB contains 4 times more RNA than DNA and RNA, while the EB contains equal proportions of RNA and DNA. The EB - RB conversion requires the alteration of the outer membrane structure by the cleavage of SS bonds. Reduction of SS bonds leads to increased membrane fluidity, increased permeability, favours the nutrients transport from the host cell and the intiation of metabolic activity. After a period of growth and division, EB is reorganized; it condenses and forms numerous EBs. Development cycle is complete, with the host cell lysis and subsequent release of EB which are initiating a new infection cycle (fig. 2). The complete development cycles, when studied in cell cultures, is taking 47-72 hours and vary depending on the strain, the host cell and the environmental conditions (Campbell & Kuo, 2004). The pathological processes due to chlamydial infection appear to be mediated by the immune reactivity. The host immune response stimulated by repeated episodes of infection increases the pathological lesions. Reinfection or persistence state causes pathological changes. Persistence of infection has been shown in different cell cultures being associated with PBs, which remain viable but not replicating, suggesting an innate ability of chlamydiae to persist intracellularly, and the mechanism by which they induce a pathological process. The factors favouring the persistence are unknown. Chlamydiae, and other intracellular pathogens, are circumventing the normal mechanisms of host cell defences. Endocitated chlamydiae are sequestered in the host cell membrane derived phagosome. The key event that allows the survival of the infectious agent in the host cell is the inhibition of phagosome–lisosome fusion. Persistently infected cultures are less sensitive to rifampicin and clortetracycline, which suggests that chlamydiae DNA transcription and translation continues in the persistent forms. In vitro , chlamydia can invade host cells deficient in nutrients and after the entry they adopt a dormant, non-infectious, but viable state. The persistence of the non-replicative stage is reversible. By adding for example, L-isoleucine, an essential aminoacid for chlamydiae and host cells is sufficient to enable development of chlamydiae. It is believed that the persistence of chlamydiae is the result of competition between host and parasitic cells for L- isoleucine. The treatment with cicloheximide, an inhibitor of host cell protein synthesis stops the competition between the host cell and chlamydiae for L-isoleucine that remains available for bacterial protein synthesis. Chlamydiae induce synthesis of interferon that has been shown to inhibit pathogen growth in cell culture. The protective immunity for Chlamydia pneumoniae and Chlamydia trachomatis infections is quite similar. Innate immunity is of key importance in primary recognition of invading pathogens. Infected epithelial cells respond in similar, but not identical ways to different invading pathogens and the pathogens are capable of modifying the host cell response (Severin & Ossevarde, 2006). Cell-mediated immunity and especially participation of type 1 Th cells are crucial for eradication or limitation of the infection at a culture negative stage. Primary infection induces development of antigen-specific immunity. Chlamydia pneumoniae is generally transmitted from person to person via the respiratory route (Kuo et al., 1995, Grayston, 2002), where mechanical barriers and innate immune mechanisms comprise the first defense systems of the host. Epithelial cells lining the trachea and nasopharynx are the first cellular barriers against inhaled pathogens. Infection of airway epithelial cells can trigger a preliminary cascade of pro- and antiinflammatory immune reactions (secretion of IL-8, and expression of the epithelial adhesion molecule-1) that initiate drifting of polymorphonuclear neutrophils (PMN) and acute inflammation. Trachoma is the leading infectious cause of blindness. Eighty-five million children have active (inflammatory) trachoma, and about 7 million people, mainly adults, are blind from late scarring sequelae (Thylefors et al., 1995). In trachoma, ocular Chlamydia trachomatis infection causes inflammatory changes in the conjunctiva, and repeated infections sometimes lead to fibrosis and scarring of the sub tarsal conjunctiva. The reasons for the heterogeneity in susceptibility to chlamydial infection and disease progression following a rather uniform bacterial exposure remain incompletely understood, but however, it has been postulated that the early secretion of proinflammatory cytokines and chemokines by epithelial cells following Chlamydia trachomatis infection may initiate and sustain a chronic inflammatory process associated with pathology (Stephens, 2003). Natividad et al. (2009) tried to investigate how genetic variation detected in IL8 and CSF2 (colony stimulating factor) could affect risk of trachoma: IL8, CSF2 and MMP9 (matrix- metallo proteinase) are co-expressed in the Chlamydia trachomatis infected conjunctiva and these gene products could interact at the site of infection to augment and sustain inflammatory processes. MMP9 enhance the activity of IL8, whereas activation of neutrophils by IL-8 may trigger the release of pro-MMP9, creating a potential for a positive feedback loop. Similarly, CSF2 release by the infected epithelial cells may mediate the influx and activation of inflammatory cells at the site of infection. Secreted CSF2 may trigger MMP9 production by monocytes, which could act to enhance and sustain the proinflammatory cascade ...