February 22, 2012
The University of Aberdeen Fungal Group has been a awarded a Wellcome Trust Strategic Award to lead a UK collaboration to bring fungal science closer to treating infection.
The new Medical Mycology and Fungal Immunology Consortium aims to train a new generation of scientists and clinicians but also to promote greater public awareness of fungal infections.
Professor Al Brown (right), a chair in Microbiology at the University of Aberdeen and Co-Director of this Consortium, also coordinates the FINSysB Network.
Read more about the award on BBC or the University website.
October 02, 2011
Dynamic environmental responses of Candida albicans that contribute to pathogenicity
Candida albicans is the most common fungal pathogen in humans, causing a variety of health problems ranging from mucosal to systemic infections. Generally harmless, it is present in 40-80% of the normal population, but in immunocompromised individuals it can proliferate and access different internal organs and tissues causing potentially fatal infections. C. albicans occupies a number of different niches in the human host. This is where the pathogen is exposed to a variety of nutrients, many of them different from more classical ones (e.g. glucose) which are the basis for most studies conducted so far. The shift from harmless commensal to opportunistic pathogen requires C. albicans’ ability to grow in poor nutrient niches and survive the diversity of stresses it encounters in the host.
Many of these stresses, such as therapeutic drugs or osmotic stress act on the cell wall of the pathogen. This is the main interface between C. albicans and its host, a multi-layered interface which proves to be extremely flexible and dynamic when exposed to different nutrients. We are studying how the variety of nutrients found in the host modulate adaptation and stress responses and how the cell wall must quickly adjust under these conditions. In doing so it relies on mechanisms of constant remodelling and maintenance of cell wall integrity. More importantly we have found that certain nutrients and in particular poor nutrient niches in the host provide a fitness advantage to the pathogen. Having adapted to these niches, C. albicans also increases its resistance to a number of antifungals, which are currently the only available weapon against fungal infections.
In this study, we show how the nutrients taken up strongly influence the cell wall architecture and hence resistance of C. albicans to certain stresses. These findings are likely to have a major impact on the behaviour of this pathogen inside the human host and may be of major clinical importance.
Adaptări dinamice la condiţiile de mediu care contribuie la patogenicitatea Candidei albicans
Candida albicans este agentul fungic patogen cel mai frecvent la om, provocând o varietate de probleme de sănătate de la nivelul mucoasei la infecţii sistemice. În general inofensiv, acest patogen este prezent în 40-80% din populaţia normală, dar în cazul persoanelor imunocompromise poate prolifera şi avea acces la diferite organe interne şi ţesuturi, provocând infecţii potenţial letale.
C. albicans ocupă diferite nişe în gazda umană, acest patogen fiind expus la o varietate de surse de carbon, multe dintre acestea diferind de zaharurile clasice (de exemplu, glucoză), care stau la baza majorităţii studiilor efectuate până în prezent. Trecerea de la comensalism la patogenicitate necesită abilitatea C. albicans de a prolifera în nişe sărace în nutrienţi şi de a supravieţui diversităţii de factori de stress întâlniţi în gazdă. Mulţi dintre aceşti factori de stress, cum ar fi agenţii terapeutici sau stresul osmotic, acţionează pe peretele celular al agentului patogen. Acesta constituie principala interfaţă dintre C. albicans şi gazdă, o interfaţă multi-strat, care se dovedeşte a fi extrem de flexibilă şi dinamică atunci când C. albicans este expus la diferiţi nutrienţi. Acest proiect studiază modul în care varietatea de substanţe nutritive întâlnite în gazda umană modulează răspunsurile de adaptare la stres şi modul în care peretele celular se adaptează continuu acestor condiţii. În acest sens, se bazează pe mecanisme de remodelare constantă şi de menţinere a integrităţii peretelui celular. Mai important, am constatat că anumiţi nutrienţi oferă un avantaj de supravieţuire agentului patogen. De asemenea, aceştia cresc rezistenţa la un număr de antifungice, care sunt în prezent disponibile ca singura arma împotriva infecţiilor fungice.
În acest studiu, vom arăta cum substanţele asimilate influenţează puternic arhitectura peretelui celular şi, prin urmare, rezistenţa C. albicans la anumiţi factori de stres. Aceste constatări pot avea un impact major asupra comportamentului acestui agent patogen în interiorul gazdei umane şi deci pot fi de importanţă clinică majoră.
September 30, 2011
There are more than 300,000 known species of fungi, but only a few of them can cause human infections. One of them, Candida albicans, is a relatively harmless organism, which can occupy the skin, oral cavity gastrointestinal tract and genitalia of healthy people. However, this fungus can take and advantage of immune system defects and cause a wide range of affections from mild superficial thrush to fatal systemic infections. There are lots of factors which make C. albicans so effective pathogen; among them are the ability to consume different nutrients (e.g. sugars) and to resist to different stresses.
September 28, 2011
Dynamics of cell wall and secreted proteins of the pathogenic fungus Candida albicans in response to clinically relevant stress conditions
September 27, 2011
Characterization of molecular mechanism used by fungal pathogens to uptake Zinc from host cells during the infection
Caratterizzazione dei meccanismi molecolari usati dai funghi patogeni per catturare Zinco dall’ospite durante il processo d’infezione.
I funghi patogeni sono una significativa causa di malattia e mortalità, la resistenza che essi sviluppano agli antifungini limita l’efficacia dei trattamenti odiernamente usati per eradicarne l’infezione. Un’interessante area di ricerca sullo sviluppo di nuove terapie per le infezioni fungine è basata sulla creazione di molecole che impediscono al fungo l’acquisizione di nutrienti dall’ospite. L´accesso ai metalli dell’ospite da parte del fungo è, infatti, uno step molto importante per il processo d’infezione; per esempio il ferro è sequestrato dall’ospite per prevenire la crescita del patogeno, in un processo conosciuto come immunità nutrizionale. Candida albicans ha sviluppato meccanismi per circonvenire questo processo e acquisire ferro dall’ospite; le basi molecolari di questo meccanismo sono in corso di studio.
September 25, 2011
In this game you take on the role of an infectious disease. You can choose between being a virus, bacteria or a parasite (no fungi though, sorry). Then you are directly thrown on a world map. Congratulations, you just infected your first human in a random region of the world. Each region is characterized by a set of variables and measures taken by the government to control your disease. Many regions have ship yards and airports that are instrumental in spreading the infection. Also, national water supplies and hospitals are important factors.
|While randomly occuring natural disasters helps you, governments will hinder you by taking increasingly drastic measures.|
The effectiveness of your disease depends basically on three variables. Lethality does exactly what it says on the box, a measure of how fast your disease kills an average human. Infectivity tells you how well the disease is transmitted and spreads through a population. Finally, Visibility determines how fast authorities react to your disease by closing airports, harbors, public transport and so on. For example, in the games term, the Ebola virus would have a high lethality, a medium infectivity but it would be very visible while HIV/AIDS would have a low visibility with medium infectivity and lethality. You can increase these variables by buying new traits with evolution points that are awarded for meeting certain milestones (number of infected, spread to a new region etc.).
|Buying new symptoms, resistances and ways of transmission will affect the three key variables in different ways.|
The game is relatively straight forward and has a good tutorial so just give it a try and see how you do. But it makes you realize how easily diseases can develop and spread. You also notice how hard the job of national and international health organizations like the WHO is to actually contain and combat a disease. So next time someone asks you what you did in your coffee break, just say you wiped out mankind. But remember, Madagaskar is always the hardest place to get. Enjoy!
July 26, 2011
Investigating new drug leads for fungal infections
Aspergillus fumigatus and Candida albicans are fungal species that can cause serious, often fatal, disease in the vulnerable, especially cancer and AIDS patients. Current medicines to treat these infections have many drawbacks including serious side effects and limited effectiveness. This project aims to find new leads in the fight against these kinds of infection. A molecular approach has been used to find proteins that are essential for the survival of both A. fumigatus and C. albicans. The theory is that if these essential proteins are disabled the fungal cells will die. Therefore it is hoped that finding chemicals that disrupt these proteins will provide chemical leads for antifungal drug discovery.
To date 3 proteins have been identified that are essential for the survival of both types of fungi. The 3 essential proteins have been made in large quantities using bacterial cells and screens are being developed to test for activity of the protein. Measuring activity of the protein in the presence of a library of small molecule compounds will enable identification of chemical inhibitors. Chemicals that disrupt both A. fumigatus and C. albicans proteins will be analysed in further detail to identify the best starting points for drug design. It is important that a new drug has the ability to enter cells in order to disrupt the protein inside the cell and cause cell death. This will be tested by mixing the chemicals of interest with whole cells to see if they can enter and then kill the cells. It is also important that the chemicals are not toxic to human cells. One way of testing this is to grow mammalian cells in a test tube in the presence of the chemicals and see if the cells stay alive. Other considerations are how easily the drug compounds can be manufactured, costs and intellectual property surrounding the work.
This study should result in new broad-spectrum antifungal drug leads to fight two of the most medically important fungi. Newer, effective antifungal medicines will result in huge benefits to human health.
July 15, 2011
June 15, 2011
Understanding the response of the human fungal pathogen Candida albicans to the attack by immune cells
Candida albicans is a fungus commonly associated with humans without causing any harm. The reason this fungus is usually harmless is because immune cells constantly patrol the sites in the body where the fungus lives; for example, the oral cavity or the gut. However, under certain circumstances, C. albicans is able to surpass the vigilance of the immune system, causing a variety of diseases ranging from superficial non-lethal manifestations to life-threatening deep-seated infections.
The purpose of this project is to understand how C. albicans is recognised and eliminated from the host. To this end, we are studying how the cells of the immune system fight against the pathogen. The key players involved in eliminating not only fungal, but pathogens in general, are phagocytes – specialised cells from the immune system which engulf and kill microorganisms. We know that C. albicans responds differently to the several kinds of cells found in blood. The cells that evoke the most dramatic response from the fungus are the so called neutrophils, cells of the immune system that play a major role in inflammation and the clearance of pathogens.
We aim to identify components of the fungal cell (proteins or enzymatic activities) that are involved in the response towards the attack by neutrophils, in order to better understand the response of the fungus and the strategies it uses to overcome and survive attack by neutrophils.
We have found that C. albicans responds in a different manner depending on whether it is inside or only touching the neutrophils. For instance, inside the neutrophils, we have observed that C. albicans produces proteins that neutralise potent oxidants that could kill the fungus. Some of these proteins are produced even before the fungus comes in contact with the neutrophil, preparing itself to encounter the oxidants and hence, survive. When the fungus is unable to produce these proteins, its survival is decreased in the presence of neutrophils. We have also observed that the fungus changes its metabolism to adapt to the nutrient-deficient environment inside the neutrophil.
Understanding the response of the fungus when confronted with phagocytes will allow us to identify the most important steps that lead to a proper response in order to contain the growth and dissemination of this opportunistic pathogen.
Candida albicans es un hongo comúnmente asociado a los humanos sin causar daño alguno. La razón por la cual este hongo es generalmente inofensivo es porque las células del sistema inmune vigilan constantemente los sitios del cuerpo donde el hongo vive, por ejemplo, la cavidad oral o el intestino.
Sin embargo, bajo ciertas circunstancias, C. albicans es capaz de evadir la vigilancia del sistema inmune, provocando una variedad de enfermedades que van desde manifestaciones superficiales no letales hasta infectiones profundas que ponen en riesgo la vida.
El objetivo de este proyecto es entender cómo C. albicans es reconocida y eliminada del huesped. Para este fin estamos estudiando cómo las células del sistema inmune luchan contra el patógeno. Los principales actores involucrados en la eliminación de patógenos en general, no solo hongos, son los fagocitos – células especializadas del sistema inmune, encargadas de atrapar y matar microorganismos. Sabemos que C. albicans responde diferencialmente a los ditintos tipos de células que se encuentran en la sangre. El tipo de células que induce la respuesta más dramática por parte del hongo son los llamados neutrófilos, células del sistema inmune que juegan un papel muy importante durante procesos inflamatorios y durante la eliminación de patógenos.
Nuestro objetivo es identificar componentes del hongo (proteínas o actividades enzimáticas) involucrados en la respuesta hacia el ataque de los neutrófilos para comprender mejor esta respuesta, así como las estrategias empleadas para superar y sobrevivir al ataque de los neutrófilos.
Hemos encontrado que C. albicans responde de formas distintas dependiendo de si se encuentra dentro o sólo en contacto con los neutrófilos. Por ejemplo, dentro de los neutrófilos, hemos observado que C. albicans produce proteínas que neutralizan potentes oxidantes capaces de matar al hongo. Algunas de esta proteínas son producidas incluso antes de que el hongo entre en contacto con el neutrófilo, preparándose para encontrarse con oxidantes y, de esta manera, sobrevivir. Cuando el hongo es incapaz de producir esta proteínas, su sobrevivencia está disminuida en presencia de los neutrófilos. Hemos observado también que el hongo cambia su metabolismo para adaptarse a las condiciones deficientes en nutrientes dentro del neutrófilo.
Al comprender la respuesta del hongo cuando se enfrenta a los fagocitos, podremos identificar los eventos clave que llevan a una respuesta correcta para contener el crecimiento y la diseminación de este patógeno oportunista.
Candida albicans ist ein Hefepilz, der häufig als harmloser Besiedler der menschlichen Haut und Schleimhäute vorkommt und unter normalen Umständen keinerlei gesundheitliche Schäden verursacht. In der Mundhöhle oder im Darm verhindern die Zellen des menschlichen Immunsystems effektiv, dass der Pilz Schaden anrichtet. Unter bestimmten Bedingungen kann C. albicans aber der Kontrolle des Immunsystems entgehen und dann verschiedenste Erkrankungen hervorrufen. Diese reichen von oberflächlichen und vergleichsweise harmlosen Verlaufsformen bis hin zu lebensbedrohlichen, systemischen Infektionen, die den ganzen Körper und verschiedene Organe betreffen.
In diesem Projekt soll daher versucht werden, die Erkennung und die Bekämpfung von C. albicans durch den Wirt besser zu verstehen. Wir untersuchen dazu, welche Mechanismen die Zellen des Immunsystems entwickelt haben, um C. albicans zu kontrollieren. Besonders wichtig sind dabei die sogenannten Phagozyten, Fresszellen des angeborenen Immunsystems, die Mikroorganismen in sich aufnehmen und dann zerstören können. Sie sind auch die ersten Immunzellen, mit denen C. albicans (und auch andere Krankheitserreger) im Wirt in Kontakt kommen sobald der Pilz in Gewebe eindringt. Dabei reagiert C. albicans in unterschiedlicher Weise auf die einzelnen Zelltypen der Immunabwehr. Besonders die neutrophilen Granulozyten, die an Entzündungsprozessen und an der Beseitigung von Pathogenen beteiligt sind, führen zu einer deutlichen Antwort des Pilzes.
Wir wollen deshalb Bestandteile der Pilzzelle (insbesondere Proteine und aktive Enzyme) identifizieren, die an der Interaktion von C. albicans mit neutrophilen Granulozyten beteiligt sind. Das soll uns ermöglichen, die Reaktionen des Pilzes besser zu verstehen – und damit seine Strategien, den Kontakt mit Immunzellen zu überleben.
Wir konnten schon zeigen, dass C. albicans – je nachdem, ob sich der Pilz im Inneren der Neutrophilen befindet oder nur an deren Oberfläche – unterschiedlich reagiert. Beispielsweise haben wir beobachten können, dass C. albicans innerhalb der Immunzellen ein Protein bildet, das Oxidantien unschädlich macht, die sonst den Pilz abtöten können. Einige dieser Proteine werden vom Pilz sogar schon gebildet, bevor er überhaupt mit Neutrophilen in Kontakt kommt. So kann er sich vor oxidativem Stress schützen und sein Überleben sichern. Ohne diese Proteine überleben deutlich weniger C. albicans-Zellen den Kontakt mit neutrophilen Granulozyten. Außerdem haben wir beobachten können, dass C. albicans seinen Stoffwechsel an die nährstoffarme Umgebung innerhalb der Neutrophilen anpassen kann.
In Zukunft wollen wir so die Reaktion von C. albicans auf Immunzellen besser verstehen und dadurch diejenigen Mechanismen identifizieren, die das Wachstum und die Ausbreitung des Pilzes im Körper ermöglichen.
April 13, 2011
March 04, 2011
To summarize, databases are a user-friendly and open access way to obtain biologically relevant information which is used worldwide in research institutes, hospitals, industries and universities.
February 25, 2011
Most scientists are specialist in a defined field so that they can focus on solving a particular problem. The problem with too much specialization is that you lose track of the big picture and neglect to integrate your research with other results. Collaborations are the remedy to this problem. If scientists encounters a phenomenon that can not fully describe by their methods and experiments in which they are specialized, they turn to other experts in their field that have access to other methods, instruments or area of expertise. Of course, as a young researcher you don't have a large network available to you but usually you are introduced by your supervisor, make contact after talks or poster sessions at conferences or just have a drink with the people you want to talk to at the hotel bar. Scientists are a very open group of people because we all share the same idealism about research and progress. The pictures in this blog post show the scientific collaborations in the World and Europe from 2005 to 2009 and are courtesy of Oliver Beauchesne and flowing data.com. Also check out the zoomable worldmap here.
Most scientific papers that are written are not the product of a single group of researchers in one lab but by a number of groups that all contribute. These contacts are mainly made during scientific conferences or in research networks (like the european FINSysB network). By pooling their resources researchers are able to produce more and better research than they could if they were working alone. The exchange of ideas is at the very core of science right next to the scientific method and peer review. So the next time you see a single scientist saving the world in his small lab without ever talking to anyone in a movie or on television, you know how likely that is...
February 11, 2011
January 31, 2011
The picture changes when C. albicans penetrates into the blood stream and/or the immune system is severely compromised as in ICU patients after major surgery or HIV patients. Here the mortality is going up to 40%, mainly because diagnostics are not fast enough and there are not enough effective antifungals available. The main problem here is that the fungal infection quickly disseminates to other organs, especially the kidneys, and destroys the tissue. In addition, in recent times Candida albicans is developing resistances to the few effective antifungals we have and evades treatment that way.
So the FINSysB consortium has several goals in which we hope to help treating clinicians as well as researchers in understanding both the inner workings of C. albicans as well as new treatment options. For that we defined four basic research areas: The "Fungal Armoury" is all about finding out how C. albicans is able to attack our cells and penetrate healthy tissue. Our body defends itself with "Defensive Shields"that kill of the fungus and prevent the infection from spreading. This battle is quite dynamic and a back and forth on the "Key Battlefields", mainly the surface of both C. albicans and our cells. Finally, we want to help to "Defeat the Enemy" by developing faster diagnostic methods, effective antifungals and ultimately a vaccine.
So have a look at our website, read about us in the European parliament magazine (page 78) or just comment if you have questions. But read our disclaimer first to avoid disappointment.
January 16, 2011
Phylo is a small flash game written by researchers from McGill University. They gave an important tool of genetic scientists, the so called Multiple Sequence Alignments, a bit more playful note. Multiple Sequence Alignments are used to see how similiar sequences from different species are and are therefore used to construct a tree of life starting from the origin of life. By seeing how similar sequences are, the relationship of species is revealed and how on species evolved out of another.
Since DNA is only composed of the four bases (Adenine, Cytosine, Guanine and Thymidine), Phylo replaces these building blocks by colored bricks. Your task is now to align two or more sequences to each other in that way that gaps in the sequence are minimized and a maximum of bricks of the same color are aligned. The program automatically scores you against a target value.
Normally this is done by computers which are good for a random aligning brute force approach but the human mind is a master in pattern recognition. Sometimes people can score higher than the computer just by intuition and a general feeling of what looks right. So to avoid spending an ungodly amount of money, they just harvest your free brainpower when you are taking a break and just wanna play something. So give it a try and see if you can help science in your lunch break.
November 25, 2010
The program Foldit is a distributed computing application (like SETI@home where unused processing time of your computer is donated to sorting through radiotelescope data.) The difference between SETI@home and Foldit is that Foldit is looking to the smaller structure and therefore inward instead of outward. Foldit tries to simulate how a protein will fold when it is finished. The computer time you donate will be used to calculate the possible and impossible conformations for the protein.
Try it for yourself and see if you like it. Maybe next time instead of solving a crossword puzzle or doing a Sudoku, try folding some proteins and help science!
November 21, 2010
In the course of his career, he developed countless microbial techniques that are still in use today. The Petri dish is named after his assistant. He identified the causative agents of Tuberculosis (Mycobacterium tuberculosis), Anthrax (Bacillus anthracis) and Cholera (Vibrio cholera). This earned him the Nobel prize for medicine in 1905.
One of his greatest contributions to microbiology was the formulation of the four Postulates that now carry his name. The postulates are step wise, each postulate based on the previous finding.
In order to establish that an organism causes a disease the following requirements have to be fullfilled:
Step 1: Association- The organism and the disease are observed together consistently.
Step 2: Isolation - The organism can be isolated from the diseased.
Step 3: Inoculation - The isolated organism causes the disease in a healthy individuum.
Step 4: Re-isolation - The organism can be re-isolated from the infected individuum.
Before Kochs discovery of the Cholera bacterium, there was a heated discussion between the Contagionists and the Anticontagionists. The Anticontagionists (Max von Pettenkoffer was one of them, see also this post) argued that in their theory human-to-human transmission was only a very minor component. They were strong opponents of quarantine and disinfection because it inhibited trade and was less effective than local solutions like improved sanitation. You can read more about it here.
Koch's Postulates proved that transmissibility played an important role in epidemics and quarantines and disinfection was indeed a suitable method to counter both. In the end, everyone benefited from the discussion because it improved both local and global safety against infectious diseases. Getting scientists to agree to something is quite difficult but using the right arguments derived from proper use of the scientific method and you have a good chance of succeeding.
Next week I will write about the central dogma of molecular biology and why it is not so dogmatic anymore.