Impact of the cytoprotective chaperone HSP25/27 on the structural integrity and autophagic degradation of chlamydial compartments

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Chlamydiae are obligate intracellular bacteria that cause sexually transmitted disease, ocular infections, and atypical pneumonia. All known chlamydia species undergo a unique biphasic developmental cycle that takes place within a non-acidified membrane-bound vacuole, termed inclusion. Chlamydiae target the host cytoskeleton to regulate diverse aspects of their intracellular survival such as the structural stability and physiological maintenance of their inclusions. To this end, the bacteria surround their vacuole with a mesh of cytoskeletal filaments, which serve as a scaffold structurally stabilizing the bacterial compartment. As a consequence, the activation of host cell defense mechanisms is limited as leakage of inclusion contents into the cytosol is prevented. We recently demonstrated that chlamydia-infected immune and non-immune cells are able to break down inclusions resulting in the cytosolic release of bacteria. Subsequently, chlamydiae are killed and degraded via autophagy leading to the processing of chlamydial antigens and their display to T cells for immunosurveillance. Moreover, we found that the infection-induced expression of the host cell chaperone HSP25/27, which regulates the remodeling of cytoskeletal filaments, seems to play a critical role in disrupting and degrading chlamydial compartments. Therefore, the detailed elucidation of HSP25/27-mediated processes in chlamydia-infected cells is crucial to understand how inclusions are attacked in host cells and which cellular machinery is used to destroy the bacterial compartments. Our key goal is to unravel the molecular and cellular processes that HSP25/27 impacts and to assess how these processes determine the outcome of chlamydial infections. We will utilize advanced state-of-the-art methods in biochemistry, microscopy, cell biology, and molecular biology to functionally characterize infection-induced HSP25/27 and attempt to identify both host cellular and pathogen-derived HSP25/27 interaction partners. We will also explore how HSP25/27 affects bacterial cytoskeleton effector proteins, and how it disrupts the integrity of persistent and productive inclusions as well as their interaction with the host cytoskeleton. Moreover, we will assess the chlamydial gene expression accompanying inclusion breakdown. Another focus of our work will address the functional cooperation between the disintegration of chlamydial compartments and their subsequent degradation. Here, we will concentrate on NOD1/2 (Nucleotide-Binding Oligomerization Domain 1/2)-pathways and on HMGB1 (High Mobility Group Box 1)-controlled processes of HSP25/27 expression and autophagy. Our studies on cytoprotective HSP25/27 and its effects on bacterial compartments will aid the deeper understanding of the intracellular life cycle of chlamydia and the development of novel therapeutic strategies against chlamydial infections.