A virus cannot make people sick unless it gets inside a living cell. Many viruses enter cells by way of carbohydrate molecules known as glycans to which they bind during the initial steps of infection. However, it is still largely unknown how glycan-mediated infection proceeds. This is about to change with a working group that has been set up by the DFG at the University of Tübingen and five other universities. The group will focus on glycovirology, a new scientific area that aims to understand the carbohydrate-related mechanisms that underlie viral infections. The project called “VIROCARB: Glycans Controlling Non-Enveloped Virus Infections”, aims in the long term to develop glycan-based, antiviral molecules for treating viral infections.
Glycovirology is such a new field of research that the term is still largely unknown to the public. This molecular biology discipline aims to characterise and resolve the interactions between viruses and glycans. Glycans are complex, long-chain carbohydrates of a broad range of shapes and sizes that are found on the surface of all cells. Glycans play a key role in intercellular communication and the transmission of signals in immune responses. Moreover, most viruses use glycans to enter cells; this allows the virus to dock on and migrate through the cell membrane. It is still largely unknown how this process works in detail.
The German Research Foundation (DFG) has therefore established a research unit called “VIROCARB: Glycans Controlling Non-Enveloped Virus Infections (FOR 2327)“ that aims to explore the role of glycans in viral infections along with the interactions between carbohydrates and selected viruses.
Prof. Dr. Thilo Stehle, director of the Interfaculty Institute of Biochemistry (IFIB) at the University of Tübingen, is the spokesperson of the research unit. Stehle and his team of researchers will study one of the viral pathogens. In addition to the researchers from Tübingen, the ambitious project also involves researchers from the Universities of Düsseldorf, Heidelberg, Lübeck and Münster and the Heinrich Pette Institute in Hamburg. The project will be funded with around three million euros for an initial period of three years.
“Sugar molecules play a crucial role in viral infections,” says Stehle. “But there are many carbohydrate structures on the surface of cells, and little is yet known about how viruses bind to them in order to gain entry into the cells. For example, there are many viruses that can jump from one organism to another. The viruses’ host-specific adaptation is based on the recognition of carbohydrate molecules. This is known as tropism and a well-known example is the influenza virus that evolves freshly in Asia every year and can jump from birds to humans. In order to do this, the virus makes what we call a switch. This means that it changes its glycan specificity.”
In their effort to understand the processes that play a role in viral infections, the research unit will initially focus on identifying glycans that can be recognised by viruses. The scientists have chosen three medically relevant viruses. These viruses are relatively easy to study as they are non-enveloped and are thus relatively small and have a simple structure. The viruses chosen were norovirus, papillomavirus and polyomavirus.
“No therapies are currently available for treating norovirus infections. Noroviruses cause severe gastrointestinal infections and are so infectious that 18 viral particles are sufficient for an infection to occur. There is no specific treatment for norovirus infections, but it is recommended to drink large quantities of water and stay well hydrated. This virus is being explored in detail by our colleagues from Lübeck,” says Stehle. “A vaccine is available against infections caused by papillomavirus, which is the second virus we are focusing on. However, the use of this vaccine is not unproblematic. Papillomavirus infections are not yet understood in detail. Papillomaviruses are important, and research into this topic will mainly be carried out in Münster.”
“The team here in Tübingen will specifically focus on polyomaviruses, which are widespread in nature. Some polyomaviruses are highly pathogenic and can cause life-threatening infections in immunocompromised patients. These include progressive multifocal leukoencephalopathy, a usually fatal disease that affects the brain, and Merkel cell carcinoma, a rare type of skin cancer with a rather poor prognosis. Treatment is not currently available for these diseases.”
All the viruses that are being studied by the researchers use carbohydrates to dock to the cell they want to infect. The researchers hope to be able to clarify the molecular process in detail over the next few years. They need to address many research questions. On the one hand, this will cover the viruses’ recognition specificity, i.e. finding out which structures the viruses recognise. On the other hand, the researchers are seeking to find out how this process can be blocked and what the consequences would be for the pathogens. They also want to find out what the virus does once it has bound to a glycan structure, and how it manages to enter the cell. “We were keen to get this project off the ground because there are now many new techniques to help us elucidate the different questions,” says Stehle, VIROCARB spokesperson and future Vice Dean for Research in his faculty.
Glycan array screening is one of the new techniques the researchers can use for their investigations. This method allows them to simultaneously screen the binding of a large number of carbohydrates to a virus. In addition, new nuclear magnetic resonance spectroscopic methods will enable the researchers to find out which carbohydrates bind to which atoms in solution. They also have new mass spectrometry techniques at their disposal as well as methods that enable the elucidation of molecule structures in general. “This is a combination of very innovative techniques, all of which are available for our large project,” says Stehle. “This is also why researchers from so many different universities are involved in the project. We needed the special expertise they offered.”
The Tübingen scientists are specialists in elucidating three-dimensional structures at atomic resolution, amongst many other things. The researchers will exchange information with each other in regular virtual meetings and video conferences. The laboratory journals will be stored on a dedicated server, which will be managed from Düsseldorf and was developed specifically for the VIROCARB project. Every project member has access to the raw data. They have also set up a website, www.virocarb.de. Another thing that the research unit will be doing is exchanging doctoral students to give up-and-coming researchers the opportunity to use the expertise and devices of institutional research partners for around three months. The researchers will also be organising a special conference for their doctoral students once a year. “We will do everything we can to make the interaction between the individual groups as smooth as possible,” says Stehle.
The long-term goal of the VIROCARB researchers is to use the findings for developing glycan-based antiviral molecules for the therapy of infections. Such molecules, which are similar to cell-surface receptors, can be administered as a solution. As the virus will bind to these molecules, it will be neutralised and blocked before it can become infectious. “It will be important to take the medicine at as early a stage as possible, so that it can act as first-line defence,” says Stehle. “However, we will first have to find out how viruses bind to such molecules. Glycovirology is still a very difficult area of research. However, with the new techniques we now hope to be able to shed light on the interactions between glycans and viruses.”