Bacteria that lead to illnesses, known as pathogens, have developed various tactics to take advantage of human cells, using them as hosts for their own benefit. Recently, researchers have revealed the strategies used by the bacterium *Chlamydia pneumoniae* (abbreviated as *C. pneumoniae*). In a recent study, they detail the molecular mechanisms that *C. pneumoniae* employs.
Pathogenic bacteria, which cause diseases, have evolved different strategies to exploit human cells as hosts for their own gain. Collaborating with healthcare professionals and specialists in structural analysis and imaging, a team of biologists from Heinrich Heine University Düsseldorf (HHU) has detailed the strategies used by the bacterium Chlamydia pneumoniae (referred to as C. pneumoniae). Their findings are published in the scientific journal Nature Communications, outlining the bacterium’s molecular tactics.
*Chlamydia* can infect both human and animal cells. For example, *C. pneumoniae* is transmitted through droplets and targets the respiratory system, leading to conditions such as bronchitis, asthma, or pneumonia. These pathogens are also associated with serious secondary issues, including Alzheimer’s disease, Reiter’s syndrome, atherosclerosis, and lung cancer.
At HHU, the research team led by Senior Professor Dr. Johannes H. Hegemann from the Institute for Functional Microbial Genomics has studied the infection mechanisms of this bacterium in collaboration with the Center for Structural Studies (CSS), the Center for Advanced Imaging (CAi), and the Institute of Biochemistry and Molecular Biology II at the Medical Faculty, under the guidance of Professor Dr. Reza Ahmadian. For the first time, they describe how *C. pneumoniae* penetrates human cells by mimicking the molecular structures of those cells—a phenomenon known as “molecular mimicry.”
The bacterium depends on being inside a host cell to reproduce. To accomplish this, it needs to trigger the cell’s transport mechanism to bring it inside through a process called endocytosis. During endocytosis, the cell membrane inwardly folds to encapsulate small material to be imported into the cell, eventually forming a vesicle that encloses the material within the cell.
A crucial element in this process is the inner component known as the actin cytoskeleton of the cell, which provides the energy required for endocytosis. This process is initiated when the human protein Cdc42 binds to a specific activator known as N-WASP.
Lead author Fabienne Kocher, a PhD student in biology and a member of the Manchot Graduate School “Molecules of Infection IV,” explains how *C. pneumoniae* manipulates endocytosis: “Once the pathogen attaches to the surface of the human cell, it injects a chlamydial protein called ‘SemD’ into its intended host. The SemD protein then binds to the vesicle’s membrane from the inside, activating the actin cytoskeleton, which causes the plasma membrane to completely engulf the large Chlamydium.”
This manipulation changes endocytosis to serve the bacterium’s interests since this process is typically not meant for transporting entire bacterial cells.
Professor Hegemann, the study’s corresponding author, comments: “We aimed to understand how various molecular structures interact and how *Chlamydia* has adapted to infect human cells as effectively as possible. The bacterial protein SemD is precisely designed to interact with N-WASP: the critical section where it binds to N-WASP closely resembles Cdc42 and has a stronger binding affinity than Cdc42 itself.”
Professor Ahmadian from the Medical Faculty adds: “We also demonstrated that SemD can even displace Cdc42, which has already attached to N-WASP, allowing SemD to bind in its place.”
To analyze the structure, the researchers cultivated tiny crystals of SemD with N-WASP and then studied their configuration. Professor Dr. Sander Smits and his team at the CSS were responsible for this work: “Complex measurements like these require state-of-the-art technology as well as skilled personnel. This level of specialized infrastructure and expertise isn’t available in every lab; thus, dedicated centers like the CSS established by HHU are essential.”
Fabienne Kocher looks forward to future developments: “We hope to create agents that can block this specific interaction between the bacterial and human proteins, effectively preventing infections by C. pneumoniae.
