Cryptococcus neoformans is the most common cause of fungal meningitis among HIV-infected individuals. While the disease is a risk for everyone with HIV who has a very low level of CD4+ T cells, researchers have discovered that those with the gene for the protein FCGR3A 158V have an immune cell receptor that binds tightly to antibody-bound C. neoformans. Perversely, this tight binding by a vigilant immune system may mean the patient's own immune system strength becomes a weakness when facing the fungus.
"We found that this high affinity Fc receptor polymorphism was very highly overrepresented in the patients that got cryptococcal disease," says corresponding author Liise-anne Pirofski of the Albert Einstein College of Medicine & Montefiore Medical Center in The Bronx, New York. Patients with two copies of the high affinity Fc receptor gene had an almost 20-fold increased risk of contracting the disease.
"It's surprising that a receptor involved with a higher capacity to bind immune complexes would be associated with susceptibility in patients with HIV," says Pirofski, since phagocytosis of immune complexes is thought of as a mechanism for fighting invading microorganisms.
Differences among Fc gamma receptors (FCGR) have already been linked to cryptococcosis susceptibility among people who are not infected with HIV, but this new information sheds light on how these receptors could influence susceptibility in HIV patients, who are at elevated risk of developing cryptococcosis and are known to have high levels of antibodies to C. neoformans. FCGRs are proteins expressed on the outsides of different kinds of immune cells, including B lymphocytes, natural killer cells, macrophages, neutrophils, and mast cells. They bind to antibodies that have grabbed onto invading pathogens, then stimulate the immune cells to destroy the invaders.
The researchers performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS), including 55 who were HIV-infected and developed cryptococcal disease, a control group of 54 who were HIV-infected and 55 who were HIV-uninfected. After correcting for a number of factors like demographics and T cell counts, they found a strong association between the gene for the high-affinity FCGR3A 158V allele and the risk of cryptococcal disease in HIV-infected men.
To figure out what that meant, they followed up with binding studies and showed that cells that express FCGR3A 158V bind more strongly to antibody-C. neoformans complexes. Greater affinity for the antibody-C. neoformans complex could increase the attachment of the fungus to monocytes or macrophages, which could in turn increase the numbers of fungi living and replicating inside immune cells. And there's also the possibility that these infected immune cells could act like a Trojan horse, delivering C. neoformans cells across the blood-brain barrier and allowing them to infect the brain. Pirofski says these possibilities are now under investigation.
C. neoformans is found all over the environment and studies show that nearly everyone is exposed to the fungus during their lifetime. However, the organism rarely causes disease in healthy people, but strikes most often in people with weakened immune systems. It is the main cause of fungal meningitis in people living with HIV, and causes devastating disease in those with profound CD4+ T cell deficiency.
But not everyone with serious T cell deficiency develops cryptococcosis, and there is currently no way of knowing which patients will develop disease. Pirofski says a test that could distinguish who is most at risk has the potential to save countless lives, particularly in sub-Saharan Africa, which is home to 69% of all people living with HIV.
"This could be the beginning of a predictive test, at least in high-risk people" says Pirofski. "I think that we're ready to study this receptor further as a risk factor for disease in larger cohorts."
mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org.
The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
Jim Sliwa | EurekAlert!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering