Tunneling Nanotubes (TNTs): An Export/Import Strategy for Chlamydia via direct Cell-to-Cell Communication

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Chlamydiae are obligate intracellular bacteria that can cause sexually transmitted diseases, ocular infections, and atypical pneumonia. These bacteria undergo a unique biphasic developmental cycle within a non-acidified membrane-bound inclusion. Chlamydiae exploit the host cell transport machinery to regulate their survival, physiological maintenance, and export from infected cells. Tunneling nanotubes (TNTs) are cellular connections that facilitate cell-to-cell transport, communication, and other physiological and pathological functions. In a recent study, we discovered that Chlamydia trachomatis-infected host cells use TNTs to export bacteria (as reticulate bodies, RBs) into uninfected neighboring cells, suggesting that these conduits play a critical role in direct cell-to-cell transmission of chlamydia. This transfer requires a functional cytoskeleton and occurs even when extracellular dissemination is impaired. The TNTs involved in the chlamydial transfer are characterized by microtubules and the chlamydial SNARE-like effector protein IncA. Although our studies provide an important insight into the TNT-mediated export of chlamydia from infected to non-infected cells, a more detailed understanding of this newly discovered exit/entry strategy is crucial. We aim to unravel the molecular and cellular processes involved in the biogenesis and acquisition/use of TNTs by Chlamydia. We will employ state-of-the-art cell and molecular biological methods to functionally characterize how chlamydia misuses and manipulates TNT formation to spread infection between neighboring cells. Additionally, we will identify cellular host and pathogen-derived proteins involved in this interaction, explore the impact of oxidative stress and stress adaptors on TNT formation and stability, and assess the involvement of chlamydial IncA protein in TNT-mediated transfer. Our work will also focus on the issues of chlamydial TNT transmission under hypoxia and in persistent cell infections induced by antibiotic treatment, where the expression and function of IncA are maintained. Our studies aim to understand how chlamydiae use intercellular communication mechanisms to export infections directly through cell-to-cell contact.