Pockets of bad bugs marked to summon cleanup crew
Many bugs that make us sick -- bacteria, viruses, fungi and parasites -- hide out in our cells in protective little bubbles called vacuoles. To clear an infection, the immune system must recognize and destroy these vacuoles while leaving the rest of the living cell intact.
The body uses a molecule called ubiquitin, here shown in red inside the box, to tag little pockets of pathogen, called vacuoles, as they bloom on the surface of a cell. The vacuole in this image is full of Chlamydia trachomatis (shown in green), the bacteria which cause a common sexually transmitted infection, but the ubiquitin molecules have marked the vacuole for destruction by the immune system.
Credit: Dr. Arun Haldar
Now, researchers have discovered that our bodies mark pathogen-containing vacuoles for destruction by using a molecule called ubiquitin, commonly known as the "kiss of death."
The finding could lead to new therapeutic strategies to boost the immune system's response to the pathogens responsible for a long list of human ailments, including tuberculosis, salmonella, chlamydia, toxoplasmosis and malaria. The study appears the week of Sept. 28 in the Proceedings of the National Academy of Sciences.
"To get rid of these pathogens, the immune system essentially has to find a needle in a haystack," said Jörn Coers, Ph.D., senior author of the study and assistant professor of molecular genetics and microbiology at Duke University School of Medicine. "It has to target a single microbe, in a vacuole, in an ocean of other membranes, floating around inside the cell. We found that the immune system accomplishes this feat by painting the vacuole with a coat of ubiquitin, which allows for the recruitment of all these other factors that viciously attack the vacuole and eliminate the pathogen inside."
When pathogens first enter a host cell, they take part of the plasma membrane with them, wrapping it around themselves like a cloak to mask their true identity. Eventually, a healthy immune system discovers the invasion and puts special molecules called guanylate binding proteins (GBPs) on high alert. These proteins specifically bind to the membranes of the pathogen-containing vacuoles and eliminate the infiltrators. Coers and his colleagues wanted to figure out how the GBPs know which membrane-bound structures to go after.
The researchers first conducted a large-scale screen for proteins involved in the clearance of pathogens. To their surprise, their search turned up a few proteins that play a role in ubiquitination, the process whereby the body's own doomed proteins are marked for destruction with the addition of ubiquitin tags. No previous studies had ever drawn a connection between ubiquitin and the destruction and elimination of pathogen-containing vacuoles by GBPs.
Coers and his colleagues decided to look for these ubiquitin tags on vacuoles containing two different microorganisms: Chlamydia trachomatis, the causative agent of the most common sexually transmitted bacterial infection, and Toxoplasma gondii, the single-celled parasite that causes toxoplasmosis.
First, they "primed" the cells with cytokines, the signaling molecules that kick the immune system into action. Then, they stained the cells with a red dye that was specific for the ubiquitin protein.
"All of a sudden we saw these beautiful rings of ubiquitin that nicely decorated the outsides of the pathogen-containing vacuoles," said Coers. He and his colleagues went on to identify the molecular players responsible both 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 showed that highly virulent strains of Chlamydia and Toxoplasma contain special factors that block the addition of these ubiquitin tags. Because their vacuoles don't get ubiquitinated, the GBPs fail to recognize them as the enemy.
In the future, the researchers would like to determine what other tricks pathogens use to evade the immune response. Once they have a clear idea of what makes some of these pathogens more dangerous, they can design therapeutics to render these hypervirulent strains more susceptible to the host response.
The research was supported by an American Heart Association Predoctoral Award (12PRE10440003), a National Science Foundation Predoctoral award, a Medical Research Council Studentship, a Boehringer Ingelheim Fonds PhD Fellowship, a Wellcome Trust Development Award, a Medical Research Council Grant (MC)UP_1202/12), and a National Institute Health Grant (R01AI103197).
CITATION: "Ubiquitin Systems Mark Pathogen-Containing Vacuoles As Targets For Host Defense By Guanylate Binding Proteins," Arun K. Haldar, Clémence Foltz, Ryan Finethy, Anthony S. Piro, Eric M. Feeley, Danielle M. Pilla-Moffett, Masaki Komatsu, Eva-Maria Frickel, and Jörn Coers. PNAS, Sept. 28, 2015. DOI: 10.1073/pnas.1515966112
Karl Bates | EurekAlert!
GLUT5 fluorescent probe fingerprints cancer cells
20.04.2018 | Michigan Technological University
Scientists re-create brain neurons to study obesity and personalize treatment
20.04.2018 | Cedars-Sinai Medical Center
At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.
Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
25.04.2018 | Physics and Astronomy
25.04.2018 | Physics and Astronomy
25.04.2018 | Information Technology