Computational Modeling of the Chlamydial Developmental Cycle Reveals a Potential Role for Asymmetric Division

Abstract:Chlamydia trachomatis is an obligate intracellular bacterium that progresses through an essential multi cell form developmental cycle. Infection of the host is initiated by the elementary body (EB). Once in the host, the EB cell differentiates into the non-infectious, but replication competent, reticulate body, or RB. After multiple rounds of replication, RBs undergo secondary differentiation eventually producing newly infectious EBs. Here we generated paired cell type promoter reporter constructs and determined the kinetics of the activities of the euo, hctA and hctB promoters. The paired constructs revealed that the developmental cycle produces at least three phenotypically distinct cell types; the RB (euoprom+), IB (intermediate body, hctAprom+) and EB (hctBprom+). The kinetic data from the three dual promoter constructs, was used to generate two computational agent-based models to reproduce the chlamydial developmental cycle. Both models simulated EB germination, RB amplification, IB formation and EB production but differed in the mechanism that generated the IB. The Direct Conversion and the Asymmetric Production models predicted different behaviors for the RB population which were experimentally testable. In agreement with the Asymmetric Production model, RBs acted as stem cells after the initial amplification stage, producing one IB and self renewing after every division. We also demonstrated that IBs are a transient cell population, maturing directly into EBs after formation without the need for cell division. The culmination of these results suggests that the developmental cycle can be described by a four stage model, EB germination, RB amplification/maturation, IB production, and EB formation.