Chlamydia, the leading cause of bacterial sexually transmitted infections, evades detection and elimination inside human cells using a cloaking device. But researchers at Duke University have grasped the hem of this invisibility cloak and now hope to break it.
To enter the cage and reproduce peacefully, many pathogenic bacteria, including Chlamydia, hide in a patch of cell membrane, forming an intracellular free-floating bubble called a vacuole or, in the case of Chlamydia, an inclusion. Chlamydia’s cloak appears to be particularly effective at evading the cell’s built-in immunity, allowing the infection to persist for months.
The Duke team, led by graduate student Steven Walsh and Jorn Koers, Ph.D., assistant professor of molecular genetics and microbiology at the Duke School of Medicine, wanted to learn how masking works.
“We knew there was an opportunity to kill Chlamydia, but when we did experiments with the human-adapted form, Chlamydia trachomatis, it grew very well in human cell cultures,” Koers said. Even after scientists used an immune booster to alert the cells’ defense systems to the presence of chlamydia, nothing happened. “We said that the causative agent is present. Our defense system must see it. Why doesn’t she see that?”
They reran their experiments using a mouse-adapted version of the Chlamydia bacteria in human cells to see how the cell immune system reacted to a nonhuman pathogen.
“People, don’t get murine chlamydia because it evolved with mice and human chlamydia evolved with humans,” Koers said. “So there’s a really precise adaptation that the pathogen has undergone.” The murine version of the bacterial inclusion was easily identified and marked for destruction in the human cells.
“Chlamydia trachomatis is so good at evading our human responses,” Koers 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. “Chlamydia adapted to mouse and man share a common ancestor,” Koers said. “However, this common ancestor may date back to a time when humans and rodents largely diverged from each other. Bacteria take a long time to fine-tune their interactions with their own kind of host.”
Working with Duke MGM colleagues Rafael Valdivia and Robert Bastidas, the researchers performed a large genetic screen of Chlamydia that identified the GarD (gamma resistance determinant) protein that appeared to block host cellThe ability to mark the inclusion of Chlamydia for destruction by the immune system.
A mutation in their GarD genes made the bacteria vulnerable. “GarD is the stealth factor,” Koers said.
Specifically, GarD interferes with the ability of a giant signaling protein called RNF213, or mysterin, to sense tiny bits of bacterial molecules sticking out of the inclusion envelope. “RNF213 is basically the eyes of the immune system,” Koers said. After blinding the mysterin in this way, the signal for immune labeling and killing is never triggered.
The inside of the cell teems with these little bubbles of membrane-covered vacuoles; most of them are friends, but some like Chlamydia inclusion, are enemies.
“There are so many different types of membranes and vacuoles that live in a cell,” Koers said. “How can the immune system find a rare vacuole containing a pathogen? In the case of chlamydia, we really don’t have an answer to that question. But whatever it is, we think this enzyme (mysterin) sees it.”
Unfortunately, that story is far from over, Koers said. It’s a remarkable new insight into a deadly infection, but just a few steps away from a cure. The researchers still need to figure out how mysterin sees these bacterial molecules in the first place and how GarD blinds the mysterin.
“If you find a mechanism to deactivate GarD, you can turn human chlamydia into mouse chlamydia,” Koers said. “This would allow us to harness the power 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, but are transmitted through sexual contact. Over time, an untreated infection can lead to inflammatory diseases of the pelvic organs, ectopic pregnancy and female infertility.
The US Centers for Disease Control recommends that young women get tested for chlamydia every year.
The bacterial effector GarD protects Chlamydia trachomatis inclusions from RNF213-mediated ubiquitination and destruction. The host cell and the microbe (2022).
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