Chlamydia, the leading cause of sexually transmitted bacterial infections, avoids detection and elimination inside human cells by using a cloaking device. But researchers at Duke University have picked up the edge of that invisibility cloak and now hope to peel it back.
To enter the cell and reproduce peacefully, many pathogenic bacteria, including chlamydia, hide in a piece of the cell membrane, forming a free-floating intracellular bubble called a vacuole or, in the case of chlamydia, an inclusion. The Chlaymydia coat appears to be particularly effective at evading the cell’s built-in immunity, allowing the infection to persist for months.
A Duke team led by graduate student Stephen Walsh and Jörn Coers, PhD, associate professor of molecular genetics and microbiology at the Duke School of Medicine, wanted to know how the cloaking worked.
We knew it had the potential to kill chlamydia, but when we did experiments with the human-adapted form, Chlamydia trachomatis, it was very good at growing in human cell cultures.”
Jörn Coers, PhD, Associate Professor of Molecular Genetics and Microbiology, Duke School of Medicine
Even after the scientists used an immune stimulant to alert the cell’s defense systems to the presence of chlamydia, nothing happened. “We said the pathogen is there. Our defense system should see it. Why doesn’t it?”
They reran their experiments using a mouse-adapted version of the Chlamydia bacterium in human cells to see how the cell’s immune system responded to a non-human pathogen.
“Humans, don’t get mouse chlamydia because it evolved with mice and human chlamydia evolved with humans,” Coers said. “So there’s this very fine-tuned adaptation that the pathogen has undergone.” The mouse version of the bacterial inclusion was readily identified and tagged for destruction in human cells.
“Chlamydia trachomatis is so good at evading our human responses,” Coers said. “It still causes an inflammatory disease, but it’s a very slow disease.”
This evolutionary arms race between the immune system and the pathogen has been going on for millions of years. “Mouse and human-adapted Chlamydia share a common ancestor,” Coers said. “However, this common ancestor can go back to when humans and rodents essentially diverged from each other. That’s a long time for bacteria to really fine-tune their interactions with their host species.”
Working with Duke MGM colleagues Raphael Valdivia and Robert Bastidas, the researchers ran a large chlamydial genetic screen that identified a protein, GarD (gamma resistance determinant), that appeared to be blocking the cell’s ability host to mark a chlamydial inclusion for destruction by the immune system.
Mutation of their GarD genes left the bacteria vulnerable. “GarD is the stealth factor,” Coers said.
Specifically, GarD interferes with the ability of a giant signaling protein called RNF213, or mysterin, to detect small pieces of bacterial molecules emerging from the inclusion shell. “RNF213 is basically the eyes of the immune system,” Coers said. After blinding the mysterin in this way, the immune destruction and destruction signal is never initiated.
The inside of a cell is full of these little bubbles of membrane-covered vacuoles; most are friends, but some, such as the inclusion of Chlamydia, are enemies.
“There are so many different types of membranes and vacuoles that live inside a cell,” Coers said. “How is the immune system able to find the rare vacuole that contains a pathogen? In the case of chlamydia, we don’t really have the answer to that question. But either way, we think this enzyme (mysterin) is seeing it. . “
Unfortunately, that’s as far as this story goes for now, Coers said. This is great new insight into a pernicious infection, but several steps away from a therapy. Researchers still need to figure out how mysterin sees these bacterial molecules in the first place and how GarD blinds mysterin.
“If you find a mechanism to turn off GarD, you can turn human chlamydia into mouse chlamydia,” Coers said. “This would allow us to harness the powers of our own immune system to clear the infection.”
New chlamydia infections occur in 200,000 Americans a year and are often asymptomatic for months or even years while being transmitted through sexual contact. Over time, an untreated infection can lead to pelvic inflammatory disease, ectopic pregnancy, and female infertility.
The US Centers for Disease Control recommends that young women get tested for chlamydia annually.
Source:
Journal reference:
Walsh, SC, et al. (2022) The bacterial effector GarD protects Chlamydia Trachomatis inclusionins from RNF213-mediated ubiquitylation and destruction. Host cell and microbe. doi.org/10.1016/j.chom.2022.08.008.