The Chlamydia microbe is the leading cause of sexually transmitted bacterial infections. In the United States alone, an average of 200,000 cases occur annually and are often asymptomatic for months or even years while they are transmitted through sexual contact. Over time, an untreated infection can lead to pelvic inflammatory disease, ectopic pregnancy, and female infertility. This germ evades detection and elimination within human cells through the use of a molecular cloaking In an interdisciplinary effort, the researchers performed an extensive genetic screening of Chlamydia that identified a protein, GarD (gamma resistance determinant), which appeared to block the host cell’s ability to ‘tag’ a Chlamydia inclusion for destruction by part of the immune system. The mutation of their GarD genes left the bacteria vulnerable. This obligate intracellular pathogen resides and replicates within a cellular compartment called inclusion, where it is protected by unknown mechanisms by interferon gamma induced cell autonomic host immunity.
But now scientists are sure that GarD is the “invisibility” factor: in particular, it interferes with the ability of a giant signaling protein called RNF213 or mysterin to perceive tiny fragments of bacterial molecules emerging from the shell of inclusion. Basically, therefore, RNF213 is like the eyes of the immune system. To enter the cell and reproduce peacefully, many pathogenic bacteria, including Chlamydia, hide in a piece of the cell membrane, forming a floating intracellular bubble called a vacuole or, in the case of Chlamydia, an inclusion. Humans do not become infected with mouse chlamydia because it evolved with mice and human chlamydia evolved with humans. So there is this truly perfected adaptation that the pathogen has undergone. The mouse version of bacterial inclusion was readily identified and labeled for destruction in human cells. This evolutionary arms race between the immune system and the pathogen has been going on for millions of years.
The mouse and human-adapted Chlamydia have a common ancestor. However, this common ancestor can trace as long as humans and rodents have essentially separated from each other. It’s a long time before bacteria fine-tune their interactions with host species. Chlamydia trachomatis is good at evading our immune responses. It still causes an inflammatory disease, but it is a very slow disease and we also know to some extent how it does. Specifically, it is the chlamydial parasitophore vacuole protein CT135 that activates the NLRP3 inflammasome via TLR2 / MyD88 signaling, as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135-mediated killing of neutrophils results in endometritis associated with macrophages in the submucosa of the endometrium. The inflammasome mediates not too violent inflammations, is involved in chronic forms by physical particles such as silica and carbon (in the case of the lungs), or by uric acid and phosphate crystals (in gout and reactive arthritis).
And it is also activated in certain genetic diseases with an inflammatory background without a bacterial or viral cause being found. This is why Chlamydia causes slow illness in almost all cases, often without fever or major symptoms. Its molecular cloak appears to be particularly effective in evading the cell’s internal immunity, allowing the infection to last for months. But now the Duke University researchers have grabbed the hem of that invisibility cloak and now they hope they can rip it off. Scientists led by Jörn Coers, PhD, associate professor of Molecular Genetics and Microbiology at the Duke School of Medicine, wanted to know how cloaking worked. Even after scientists used an immune stimulant to alert cellular defense systems to the presence of Chlamydia, nothing happened. So the researchers wondered: “The pathogen is there. The immune system should see it. Why doesn’t it see it?” They therefore experimented using a mouse-adapted version of the Chlamydia in human cells.
Having blinded Mysterin in this way, the signal of immune weakening and destruction is never triggered. RNF213 is a ubiquitin-ligase, an enzyme induced by interferon gamma that “labels” target proteins to facilitate their cellular elimination. Well, this enzyme facilitates the ubiquity and destruction of GarD-deficient inclusions. The inside of a cell is teeming with these membrane-covered vacuoles; most are produced by the cells themselves. But with regard to those produced by microbes such as the inclusion of Chlamydia, there is an unanswered question: there are so many different types of membranes and vacuoles that live inside a cell. How is the immune system able to find the rare vacuole that contains a pathogen? In the case of Chlamydia, researchers still don’t have the answer to this question. But whatever it is, they believe this enzyme (mysterin) is seeing it.
Researchers have yet to understand how mysterin views those bacterial molecules in the first place and how GarD blinds mysterin. Finding the answer means developing new molecules or antibiotics that can finally get rid of Chlamydia by making it visible to the immune system.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Walsh SC et al. Cell Host Microbe 2022 in press.
Yang C et al. Nat Commun 2021 Sep 15; 12(1):5454.
Darville T. J Infect Dis. 2021; 224(12 Suppl 2):S39-S46.
Wang X et al. Infect Immun. 2020; 88(8):e00198-20.
Dott. Gianfrancesco Cormaci
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