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Molecular kiss of death flags pathogens

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Malaria Red Blood Cells

Bacteria, viruses, fungi and other such bugs and parasites that make us sick hide in our body cells in certain protective bubble shells called vacuoles. For the body to fight and clear an infection, it should have the ability to recognize and destroy these vacuoles without affecting the rest of the living cell.

In a new study, the results of which appeared recently in the Proceedings of the National Academy of Sciences, researchers have discovered that our bodies mark pathogen-containing vacuoles for destruction by using a molecule called ubiquitin, also commonly referred to as the “kiss of death.” The findings are promising as it can lead to the creation of new therapeutic strategies to boost the immune system’s response to the pathogens that lead to human ailments, like tuberculosis, salmonella, chlamydia, toxoplasmosis and malaria.

Jörn Coers, Ph.D., senior author of the study and assistant professor of molecular genetics and microbiology at Duke University School of Medicine opined that for the body to find and get rid of these pathogens, it is like finding a needle in a haystack. The immune system must target a single microbe, in a vacuole, in an ocean of other membranes that are floating around inside the cell. The immune system does this humongous task by painting the vacuole with a coat of ubiquitin, which lets it attack the vacuole and eliminate the pathogen inside.

It is interesting to know how the whole thing happens “ a pathogen when it enters a host cell cloaks itself with a part of the plasma membrane to hide its true identity. If our immune system is healthy, it will eventually discover the invasion and will place special molecules called guanylate binding proteins (GBPs) on high alert. These proteins are special because they just bind to the membranes of the pathogen-containing vacuoles and eliminate the invaders. Coers and his fellow researchers were curious to find out how the GBPs know exactly which membrane-bound structures to seek out.

A large-scale screen for proteins involved in the clearance of pathogens was carried out by the researchers. Surprisingly, they found a few proteins that play a role in ubiquitination, the process by which ubiquitin tags are put on the body’s own doomed proteins so that they can be destructed. No other previous studies had correlated ubiquitin and the destruction and elimination of pathogen-containing vacuoles by GBPs.

To further their study, Coers and his fellow researchers went ahead and looked for these ubiquitin tags on vacuoles containing two different microorganisms – Toxoplasma gondii, the single-celled parasite that causes toxoplasmosis and Chlamydia trachomatis, the causative agent of the most common sexually transmitted bacterial infection. The first thing they did was to prime the cells with cytokines “ they are signaling molecules that kick the immune system into action.  The cells were then stained with a red dye that was specific for the ubiquitin protein.

Coers said that suddenly they could see the beautiful rings of ubiquitin nicely decorating the outsides of the pathogen-containing vacuoles. They then went on to identify the molecular players responsible for attaching the ubiquitin tags and for escorting the GBPs to the surface of the vacuole so they can coordinate an attack. The researchers also found that highly virulent strains of Chlamydia and Toxoplasma contain special factors which block the addition of these ubiquitin tags. Since their vacuoles don’t get ubiquitinated, the GBPs don't treat them as invaders.

Further research is needed to determine what tricks pathogens resort to, to evade the immune response. Once it is ascertained what makes some of these pathogens more dangerous, therapeutics can be designed to render these hypervirulent strains more susceptible to the host response.