Chlamydia is the most common bacterial sexually transmitted infection in the world, with 150 million people infected in 2023. Although the infection can be treated with antibiotics, it often leads to infertility and other health problems.
A safe and effective chlamydia vaccine would help prevent asymptomatic but transmissible infections that often go undiagnosed. For 40 years, researchers have been working to develop such a vaccine, but an effective candidate has remained elusive.
New research in Nature Communications - conducted by a team from Lawrence Livermore National Laboratory (LLNL), UT Southwestern Medical Center, Ligo Analytics, the University of California, Irvine and the University of California, Davis - provides the first high-resolution images of protein structures in the outer membrane of chlamydia.
The result reflects LLNL's broader biosecurity mission, as understanding the structure of dangerous or hard-to-treat pathogens at the atomic level supports the nation's ability to detect, defend against and respond to biological threats. It could be a gamechanger for vaccine development.
"Vaccines work best when they teach the immune system to recognize an antigenic protein exactly as it appears in nature," said LLNL scientist and author Matthew Coleman. "If scientists know the precise shape of a protein on the surface of a bacterium, they can design vaccines that look more like the real thing."
The images were taken of major outer membrane proteins, or MOMPs. Many vaccines work by introducing harmless components of a bacterium or virus like a MOMP to elicit an immune response in the human body.
But when chlamydia MOMPs are broken down and reassembled without their natural shape, they have not triggered a strong enough immune reaction for a viable vaccine. The new study indicates that the proteins' structure may be critical for creating the protective immune response.
Until now, MOMPs have been very difficult to extract from bacteria and image. By carefully isolating MOMPs and using cryo-electron microscopy to freeze and probe them with an electron beam, the authors revealed the protein's shape for the first time at atomic resolution.
LLNL researchers played multiple roles across the project. Coleman, who co-led the National Institutes of Health (NIH) project with Luis de la Maza of the University of California, Irvine, helped supply the chlamydia samples used for imaging and coordinated the team. LLNL scientists analyzed and interpreted the cryo-electron microscopy data, using it to build maps of the MOMP.
The team showed that MOMPs form in groups of three, coming together into a tripod shape. A large, folded cluster of antigens sits on top of the tripod like a mushroom cap. Those antigens are what antibodies in the immune system recognize and attack.
"The biggest message from this work is that shape matters," said Coleman. "For years, scientists knew MOMP was an important vaccine target, but they did not know exactly what it looked like or important components of the protein for generating protection. This study provides the first detailed picture of its natural structure and shows how protective antibodies recognize it."
This same approach can be used to study other important proteins from the surface of gram-negative pathogens, leading to better understanding of biothreats and potential vaccines for many infectious diseases. The group is now working to design isolated MOMPs that follow their naturally folded three-dimensional structures.
This project was funded in whole or in part with federal funds from the NIH. Other LLNL authors include Brent Segelke, Beverly Robinson, Patrik D'haeseleer and Megan Shelby, who led the LLNL structural analysis efforts.
