Evasion of apoptosis and immune recognition during host adaptation of Chlamydia and Chlamydia-like bacteria

• Applicant: Professor Dr. Georg Häcker
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268633228

Chlamydia is a human-pathogenic bacterium and can accordingly infect and replicate inside human host cells. Chlamydia has evolved from an early endosymbiont that at one stage infected single-celled organisms. Another group of present-day bacteria that have evolved from the same early precursor are known as Chlamydia-like bacteria (e.g. Parachlamydia), which grow in free-living amoebae. It has recently been found that Parachlamydia induces cell death by suicide (apoptosis) in insect cells, and that this is the reason for the inability of the bacteria to grow in these cells in culture. We have found that infection-induced apoptosis also occurs in mammalian (mouse and human) cells. This suggests that insect and mammalian cells have, during evolution from a single-celled organism, acquired means to detect Parachlamydia and to undergo apoptosis, most likely as a matter of self-defence ("cell-autonomous immunity"). Mechanistically, this implies receptors that recognize the bacteria and that then activate a signalling pathway to apoptosis. During evolutionary adaptation, human-pathogenic chlamydiae appear to have found ways of escaping this recognition and cell death induction, enabling growth in human cells (Chlamydia also can grow to a degree in insect cells). In this project we will test this hypothesis and endeavour to work out the relevant molecular framework. Starting from the initial observation of apoptosis induction and from preliminary data on how apoptosis is induced we will identify components of the signalling pathways that are necessary for apoptosis induction by Parachlamydia. We will further test for the requirements of upstream signalling components that are required for the recognition of Parachlamydia, leading to the activation of the core apoptosis machinery. These experiments will be conducted in insect (Drosophila) and in mouse or human cells in cell culture, using in particular cell lines deficient in a variety of signalling proteins. Comparison of different cell types will further narrow down the circle of possible recognition systems that may be involved. By comparative studies using Chlamydia we will endeavour to work out the differential mechanisms that are activated and that either permit growth or lead to apoptosis. We hope that this will in turn permit the identification of systems critical for this form of immune evasion in bacteria that are adapted to metazoan hosts equipped with more sophisticated defence systems than protozoa (such as Chlamydia). Established results will be further strengthened by the use of other candidate bacteria from the order Chlamydiales of known host range. We believe that this project will provide us with substantial information on mechanisms and importance of the evasion of cell-autonomous immunity against obligate intracellular bacteria as well as signalling upon recognition of chlamydiae.

• DFG Programme: Research Grants