Regulation of Attachment and Early Intracellular Development of Chlamydia trachomatis in Eucaryotic Cells

• The obligate intracellular bacterium, Chlamydia trachomatis , a common human pathogen, causing different diseases in both males and females, as well as in infants born to infected mothers. Occasionally, these diseases involve serious complications, such as blindness and infertility. C. trachomatis has a unique biphasic life cycle: after initial inclosure in membrane~bound endosomes, the infectious elementary bodies (EBs) reorganize to the metabolically actiVe forms (RBs); the RBs divide by binary fission, and after multiple divisions, they again differentiate to form new EBs, which are subsequently released from the host cell to start a new infectious cycle. As an attempt to investigate the early events of chlamydial infection, my results show that EBs bind with high affinity to collagen type I and heparan sulfate, suggesting that this selective affinity may mediate the attachment of chlamydiae to the surface of a host cell. ER-containing endosomes avoid fusion with host celllysosomes. However, within 30 min of form ation, these endosomes form one local aggregate in the central orperinuclear region of individual cells. This aggregation is reversible and time and temperature dependent, and requires viable EBs. Clathrin and F-actin are mobilized and colocalized with EB aggregates, suggesting that the aggregation of EBs is an active process that may be biologically involved in the infectivity of chlamydiae. The aggregation and inclusion formation of EBs, and the redistribution of F-actin seem to be controlled by both extra- and intracellular Ca2+, whereas the attachment and ingestion of EBs occur independently of Ca2+ in the growth medium and at low intracellular free Ca2+ [Ca2+]i. Moreover, chlamydiae do not induce any changes in the level of [Ca2+]i, this indicates that the aggregation of EBs requires a normal homeostasis of intracellular Ca2+. By affecting F-act:in reorganization and, putatively, certain Ca2+ -binding proteins, [Ca2+]i plays a vital role in the process of chlamydiae infection. The ca2+_ and phospholipid-binding proteins, annex.ins, are selectivelytranslocated during ehlamydial infection, i.e. annexins III, IV, and V, but not annexins I and VI, translocate to the proximity of chlamydial aggregates and inclusions. Annexins differ in their ability to associate with chlamydia-containing vesicles and inclusions. This fact implies that different factors regulate the interaction of annexins I and Ill with the membrane and also suggests that there is a selective regulatorymechanism that guides endosome aggregation and that is responsible for endosome avoiding lysosome fusion during chlamydial infection. Chlamydiae also induce mobilization of intracellular Ca2+ stores. This suggests that in a chlamydia-infected cell localized [Ca2+]i changes may occur by mobilization of Ca2+ stores at the sites of ca2+ action. The physiological role of ca2+ stores redistribution during infection of the host cells with chlamydiae might be to generate subceJlular [Ca2+]i gradients needed for the intracellular itinerary of the membrane trafficking of BE-containing endosomes.

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