There are two types of chlamydia that affect humans: Chlamydia trachomatis and Chlamydia pneumoniae (Cpn). While the former cause venereal diseases, Cpn lead to acute infections of the upper and lower respiratory tract. In addition, they are associated with various chronic diseases such as bronchitis and asthma and also with lung cancer, but also with Alzheimer's dementia and atherosclerosis. The majority of Germans will be affected by these bacteria in the course of their lives.
To get into the human cell, the chlamydia must first overcome its boundary, the so-called plasma membrane (PM). The membrane consists of a double layer of lipids with embedded proteins. By indenting areas of the PM, the cell can absorb liquid and particles from the environment into the interior of the cell, which is referred to as “endocytosis”.
Pathogens such as chlamydia, which must also get inside the cell, outwit the endocytosis mechanism for their purposes. The working group of Prof. Dr. Johannes Hegemann at the HHU Institute for Functional Genome Research in Microorganisms has now identified a chlamydial protein that plays a crucial role in the penetration of Cpn into the human cell: his name is SemC; its discoverer is Dr. Gido Murra from Prof. Hegemann's group.
In a first step, the chlamydium manages to inject SemC into the host cell. The colleagues from the Pasteur Institute in Paris were able to show that SemC is transported directly from the bacterium into the cell interior via a protein needle used by many pathogenic bacteria. Once there, the protein binds to the inner plasma membrane and changes its structure locally. This changes the shape of the membrane: it becomes more curved. In addition Dr. Katja Mölleken: "With SemC we have discovered the first protein of an infectious agent that is able to change PM in this way."
The stronger membrane curvature triggered by SemC now leads to the binding of the body's own protein SNX9 at this point, where it binds both to the curved membrane and to the SemC located there and further increases the curvature. SNX9 is a protein essential for the endocytosis processes of the human cell by building up the actin cytoskeleton on the invading PM. The SemC-mediated SNX9 binding to the PM now allows the chlamydium to penetrate into the cell from the outside at the curved location of the PM by endocytosis and to multiply further inside the cell. "The structure of the PM of the host cell is therefore an important factor in enabling the infection of a cell by the pathogen," emphasizes Dr. Sebastian Hänsch. Dominik Spona adds: "This way, the bacterium virtually creates its own door into the cell."
The research group has found another important piece of evidence for the interaction between SNX9 and SemC induced by Cpn. The colleagues at the German Center for Neurodegenerative Diseases in Munich created human cells in which the amount of SNX9 protein had been greatly reduced. Dominik Spona: "With these cells, it was significantly more difficult for Cpn to overcome the plasma membrane using endocytosis and to infect the cell."
The discovery opens up new opportunities to treat a chlamydial infection or to develop targeted vaccines that repel the bacteria at an early stage. Working group leader Prof. Hegemann: "Once the exact mechanism has been decoded, there are possible points of attack at which this mechanism can be blocked, for example by preventing the SemC binding to the PM or to the body's own SNX9 protein."
The research work in Düsseldorf took place as part of a Manchot doctoral scholarship and a doctoral scholarship from the Düsseldorf Entrepreneurs Foundation. Other parts were created as part of a collaboration between the Düsseldorf Collaborative Research Center 1208 and the Center for Advanced Imaging.
Reference: Sebastian Hänsch, et al. (2020) Chlamydia-induced curvature of the host-cell plasma membrane is required for infection, Proc Natl Acad Sci US A. . DOI: 10.1073 / pnas.1911528117
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