Jan Rehwinkel: How the innate immune system detects flu virus
The first arm of our immune response is triggered by the detection of the presence of the virus. RIG-I protein is an intracellular receptor that detects the presence of viral genomic information. A better understanding of these mechanisms might help us develop better vaccination strategies.
Q: What is special about flu virus?
JR: Flu is a virus we call influenza A virus in the lab, and it causes annual epidemics. But what is actually really special about this virus is that we are under the constant threat of a new highly pathogenic, very dangerous virus emerging and this virus could cause a pandemic outbreak. What causes these highly pathogenic viruses to emerge sometimes? Flu has a very special property in that it not only infects us as humans but also a number of different animals including pigs, chickens and other birds. In addition to that, flu has a very special way of storing its genetic information. The genetic information of this virus is contained in 8 pieces that we call genome segments, and what this virus can do is swap individual genome segments between different virus isolates. If that occurs between viruses that infect us and then infect chickens or other birds for example, then there is a chance that a very highly pathogenic, very dangerous virus is emerging.
Q: What is our immune response to flu?
JR: Our immune response starts initially when our cells in our body detect the presence of the virus and the immune response that then ensues can be divided into two different stages. The first stage is called the innate immune response and this very rapidly starts upon infection and often helps to contain the spread and propagation of the virus. A little bit later, the second step starts and that is called the adaptive immune response. The adaptive immune response is characterised by being very specific at targeting the virus that infects us. If everything goes well the adaptive immune response clears the virus from our system. What has emerged over the last few years is that the second wave of the immune response, the adaptive immune response, is not only started but also instructed and directed by the first wave of the immune response, the innate immune response, and that in turn is started by the initial detection of flu virus. So we've decided to study that very first step, the initial detection of the virus by the cells in our body. We know that our cells have proteins called receptors and these receptors recognise the presence of viruses, and we're working on one particular receptor called the RIG-I protein. This RIG-I protein detects the presence of influenza virus and what we've recently discovered is that RIG-I detects the presence of the virus by sensing the presence of genomic information from this virus.
Q: And how does this receptor distinguish the viral genetic material from our own?
JR: Our cells contain lots of genetic information that is contained in a molecule called DNA which is related to the RNA genome of the virus. This DNA of our own cells is then transcribed into RNA, into messenger molecules, which are eventually translated into proteins that realise the genetic information. So that means that our cells already in the absence of a virus contain quite a high amount of RNA. So how can this RIG-I receptor that we are working on distinguish between the RNA of a normal uninfected cell and the RNA genome that comes in when a virus such as flu infects these cells? What we have found out is that the difference lies at one of the ends of these RNA molecules: cellular RNA contains a structure called cap structure which is a small chemical modification at one end of these molecules. However the RNA from the virus lacks this cap structure and what RIG-I, the immune sensor, is actually recognizing is the presence of RNA that lacks these cap structures as found in the genome of influenza virus. That is an explanation for why this receptor only starts an immune response when actually a virus has infected our cells and not in the absence of virus infection.
Q: What are the most important lines of research that have developed over the past 5 – 10 years?
JR: Many people have studied the second wave of the immune response, the adaptive immune response, for many decades. But what's come more to a realisation recently is that the innate immune response that precedes the adaptive immune response as the first wave of defence is not only important for starting the adaptive immune response but in fact also shapes and instructs the outcome of the adaptive immune response. So the innate immune response is very important. Progress over the last 5 to 10 years has revealed a number of receptors that detect different infectious micro-organisms - not only viruses such as the influenza but also bacteria or parasites. Despite this progress there's much to be learned about how these receptors detect individual pathogens and what effects they bring about in the innate and eventually adaptive immune response.
Q: Why does your line of research matter, why should we put money into it?
JR: Flu is a very important virus to human health – annual seasonal epidemics alone kill around half a million people worldwide. If a new highly pathogenic very dangerous pandemic virus were to emerge, that could kill many more people. So we believe that understanding how the immune response, during the influenza virus, is initiated and triggered by the receptors that we are working on, we would get some ideas about how to influence and control the immune response in infected humans. In addition to that we believe this knowledge about immune response to flu will also help us to develop better vaccination strategies for flu virus. Beyond that flu is not the only virus that infects humans, for example 30 million people worldwide are infected with HIV-1. This is a different virus but there are also immune receptors in our cells that recognize the presence of this virus and start an immune response. However that is not very well understood and we are now trying to expand our research to study how HIV-1 is detected given that it is so important for human health.
Q: How does your research fit into translational medicine within the department?
JR: We are overall studying how viruses such as flu or HIV-1 are recognised by the innate immune system, and that would have impact on managing infectious disease and on managing vaccinations. But there is also another aspect to it: humans often suffer from autoimmune diseases such as Lupus. In these diseases you have a situation that could be described as 'friendly fire' where our immune response is started although no virus or no infectious micro-organism is present. We believe by understanding the mechanisms of how immune responses are triggered during virus infections you may also get some insights in understanding why these responses are triggered inappropriately in these autoimmune diseases. We are hoping to extend our research from not only studying the recognition of viruses but also to understanding why immune responses are aberrantly triggered in autoimmune diseases.