Chlamydia, the leading reason for sexually transmitted bacterial infections, evades detection and elimination inside human cells by use of a cloaking device. But Duke University researchers have grasped the hem of that invisibility cloak and now hope they’ll pull it apart.

To enter the cell and peacefully reproduce, many pathogenic bacteria, including Chlamydia, cloak themselves in a bit of the cell’s membrane, forming an intracellular free-floating bubble called a vacuole or, within the case of Chlamydia, an inclusion. Chlaymydia’s cloak appears to be especially effective at evading the cell’s built-in immunity, allowing the infection to last for months.

A Duke team led by graduate student Stephen Walsh and Jörn Coers, PhD, an associate professor of molecular genetics and microbiology within the Duke School of Medicine, desired to know the way the cloaking worked.

We knew there was the potential to kill Chlamydia, but once we did experiments with the human-adapted form, Chlamydia trachomatis, it was superb 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 of the presence of Chlamydia, nothing happened. “We said, there’s the pathogen. Our defense system should see it. Why does it not see it?”

They ran their experiments again using a mouse-adapted version of the Chlamydia bacteria in human cells to see how the cell’s immune system responded to a non-human pathogen.

“Humans, do not get mouse Chlamydia since it evolved with mice and human Chlamydia evolved with humans,” Coers said. “So there’s this really fine-tuned adaptation that the pathogen has undergone.” The mouse version of the bacterial inclusion was readily identified and labeled for destruction in human cells.

“Chlamydia trachomatis is so good at evading our human responses,” Coers said. “It still causes an inflammatory disease, however it’s a really slow disease.”

This evolutionary arms race between the immune system and the pathogen has been happening for hundreds of thousands of years. “Mouse and human adapted Chlamydia have a typical ancestor,” Coers said. “Nevertheless, this common ancestor may return so far as when humans and rodents principally split from one another. That is an extended time for the bacteria to essentially fine-tune their interactions with their host species.”

Working with Duke MGM colleagues Raphael Valdivia and Robert Bastidas, the researchers ran a big genetic screen of Chlamydia that identified a protein, GarD (gamma resistance determinant), that seemed to be blocking the host cell’s ability to mark a Chlamydia inclusion for destruction by the immune system.

Mutating their GarD genes left the bacteria vulnerable. “GarD is the stealth factor,” Coers said.

Specifically, GarD interferes with the power of a large signaling protein called RNF213 or mysterin to sense small bits of bacterial molecules poking out of the shell of the inclusion. “RNF213 is essentially the eyes of the immune system,” Coers said. Having blinded mysterin on this fashion, the signal for immune flagging and destruction isn’t began.

The inside a cell is swarming with these little bubbles of membrane-covered vacuoles; most are friends, but some, just like the Chlamydia inclusion, are foes.

“There’s so many differing kinds of membranes and vacuoles that live inside a cell,” Coers said. “How is the immune system in a position to find the rare vacuole that comprises a pathogen? Within the case of Chlamydia, we actually haven’t got the reply to that query. But whatever it’s, we imagine this enzyme (mysterin) is seeing it.”

Unfortunately, that is all of the further this story goes for now, Coers said. That is an awesome recent insight right into a pernicious infection, but several steps away from a therapy. Researchers still have to determine how mysterin sees those bacterial molecules in the primary place and the way GarD blinds mysterin.

“In case you could discover a mechanism to deactivate GarD, then you definately can turn human Chlamydia into mouse Chlamydia,” Coers said. “That will allow us to harness the powers of our own immune system to clear infection.”

Recent Chlamydia infections occur in 200,000 Americans per yr and are sometimes asymptomatic for months and even years while being transmissible through sexual contact. With time, an untreated infection can result in pelvic inflammatory disease, ectopic pregnancy and feminine infertility.

The US Centers for Disease Control recommends that young women be tested for Chlamydia annually.

Source:

Journal reference:

Walsh, S.C., et al. (2022) The Bacterial Effector GarD Shields Chlamydia Trachomatis Inclusoins from RNF213-Mediated Ubiquitylation and Destruction. Cell Host & Microbe. doi.org/10.1016/j.chom.2022.08.008.