The complex relationship between viruses and our immune system

 Virus Appreciation Day, celebrated annually on 3 October, serves a dual purpose: to foster respect and understanding for viruses while raising awareness about their serious impacts on health. To mark the day, Professor John Tregoning from Imperial’s Department of Infectious Disease shares valuable insights into influenza viruses, highlighting their effects, the importance of vaccination, and ongoing research for universal vaccines against evolving strains in our latest blog.

Viruses have an enormous impact on human health, but they don’t only infect humans. Many viruses also infect animals, plants and even bacteria. Some viruses are quite promiscuous, infecting a wide range of animal species before passing on to humans through a process known as zoonotic transmission. One of the most problematic of these zoonotic infections is influenza virus.

The main natural reservoir of influenza virus is wild birds, particularly ducks and geese. The virus can then transmit from these birds into domestic poultry, like chickens, and to livestock, such as pigs, before ultimately reaching people. In the past five years, a new strain of avian influenza has emerged with an ability to infect an even wider range of mammalian species. It has been detected in cattle in the US.

Influenza, the disease caused by the virus, poses a substantial health burden. It resulted in nearly 15,000 deaths in the UK in the 2022-23 winter season. As well as death, it is a significant cause of hospitalisation and general illness – with a long tail of recovery. Additionally, influenza infection doubles the risk of heart attacks and strokes for up to a year after illness. Given these risks, getting an influenza vaccine this time of year is highly recommended. As I discovered researching my latest book Live Forever one of the simplest ways of extending your life is through vaccination. A vaccine will give you protection against the most severe forms of disease caused by the virus and protect you against subsequent illness.Vaccines train your body to recognise pathogens and fight them off. To do this, they make use of a facet of immunity called immune memory. When re-exposed to the same virus, your immune response activates faster and stronger, stopping the infection in its tracks. Several aspects of immune memory can prevent subsequent infections, but an important one are antibodies – this is a type of protein that is highly specific in what it can recognise and bind. When you are immunised with influenza vaccine, you make influenza virus specific antibodies that can stop the virus from infecting you.

However, influenza virus is a tricky customer. It changes its coat in an attempt to escape antibodies and this means that the vaccine can become outdated – necessitating boosters each year. These different types of virus are called different strains. A huge goal in influenza vaccine research is to make a vaccine that can recognise a wider range of different influenza virus strains, even as they mutate to evade the immune response. These are called universal influenza vaccines; ideally you would be able to have a single immunisation and get lifelong protection.

But there are a number of potential hurdles in the path to developing such a vaccine, these relate to the virus itself, but also how our immune system works and forms memory. One facet of the immune response that we have been investigating recently is called ‘original antigen sin’ – which is not a particularly catchy name. What it refers to is how the first exposure to a series of similar looking viruses affects subsequent responses. It’s a bit like how babies learn to recognise people – the first woman a baby recognises might be called mummy and subsequently they might refer to all women as mummy (at least for a while). In the case of original antigen sin, the immune system may focus on familiar elements of different viruses at the expense of recognising new or changing parts, leading to inefficiencies in responding to variations.

 The problem with studying this is that human’s exposure to influenza is extremely complex – we have all been infected at different times with different viruses, some of us will then mix this up with a vaccination leading to a natural history of disease that is very hard to interpret. In our most recently published work in The Journal of Infectious Disease, we used a different approach to understand the immune response to influenza infection. Through a collaboration with the pharmaceutical company Sanofi, we performed experiments on a type of mouse called the Kymouse that has been genetically engineered to make human like antibodies. This allowed us to explore how antibodies change following infections with different strains of influenza virus. Our studies suggested that infection with one strain can affect the response to a subsequent infection.

Want to Learn more?

This complex interplay of virus and human immune response is an endlessly fascinating subject, unlocking its secrets can help us identify new ways to protect humans (and chickens) from infection with a deadly virus. But don’t restrict yourself to learning about it on Virus Appreciation Day – if you have found your appetite whetted – why not try our FREE massive open online course called Foundations in Virology and Vaccinology. It does exactly what it says in the link, giving an overview of viruses and vaccines, what we know about them and what we hope to discover.

Starve a cold

 

One thing you have probably noticed when you have an infection is a profound loss of appetite? In healthy adults, this could be seen as something of a blessing, it can have much more serious consequences, particularly at the extremes of age. In the elderly, the after effects of respiratory infections can accelerate frailty and the loss of independence. In the very young, not feeding can lead to dehydration and possibly contributes to more severe disease.

In previous studies, we observed that the loss of appetite was associated with the immune response to infection. We were interested as to what might drive the loss of appetite – with a view that understanding how it occurs might lead to approaches to reverse it. In particular we wanted to understand one component of the immune response – the cells that are recruited to the lungs to fight off infections and the way that they communicate with other cells.

In our recently published study we looked at one of the signals produced by immune cells, a molecule called Interleukin 1 alpha (IL-1α for short). Cells release IL-1α to warn the rest of the body that an infection is happening and as a way of recruiting reinforcements to help in the fight. We saw that the peak of IL-1α release into the lungs just precedes the weight loss, and therefore suspected it played a role. To test our hypothesis (IL-1α causes weight loss during infection) we took two approaches. Firstly, we blocked it during the course of infection; when blocked there was no weight loss. Secondly, we added IL-1α by itself; when we did this, we observed weight loss. Put together, these observations strongly suggest that IL-1α released by immune cells reduces the appetite, and leads to weight loss.

We then looked deeper into how this might happen. And we found a really striking result – IL-1α levels increase in the brain during infection. We think this is linked to an increase in permeability between the brain and the rest of the body, which allows molecules to enter the brain which would otherwise normally stay outside. The IL-1α in the brain then triggers a cascade of hormones, in particular one called leptin, which is linked to feelings of satiety (if leptin goes up, you feel full and stop eating). Famously mice lacking the leptin gene are enormously fat because they never stop eating.

One other curiosity in our results was that when the mice stop eating, the bacteria in their guts change. These changes increase certain families of bacteria – some of which are linked to recovery from infection. This suggests the intriguing possibility that there is a protective value in not eating when you have a cold, because it increases protective bacteria – we have yet to explore this fully.

Overall, we have dissected a pathway that links the immune response to infection to a loss of appetite and discovered a key appetite regulatory role for an immune molecule IL-1α. The next step is to explore how this can be approached therapeutically.

St Mary’s Medical School: End of a chapter

As the Faculty of Medicine prepares for the full decant of the St Mary’s Medical School building, Professor John Tregoning, Professor in Vaccine Immunology in the Department of Infectious Disease, takes a trip down memory lane, reflecting on almost 20 years spent working in the “site steeped with history”.

On the 1^st of August 2024, as part of a wider departmental move, I will leave the St Mary’s Hospital campus having worked there for nearly half my life. As such, it felt like time to reflect.

I first crossed the threshold when the St Mary’s medical school had just merged with Imperial in 1999, visiting friends who were studying there. Admittedly, it was not in an academic capacity. I went to the long-closed, but legendary bar in the basement (allegedly it closed because seeing future doctors heavily inebriated was off-putting to those visiting the hospital). I don’t remember much of that night, a fact I am putting down to time passed, rather than beers consumed.

The red, red bricks of Praed Street

Time moved on, and in 2003 I passed back through the black metal gates and under the bridge linking the St Mary’s Medical School building with Sir Alexander Fleming’s old lab. Thus beginning a 20-year association with Praed Street. I started there as a newly qualified post-doc (a professional scientist), the ink barely dry on my PhD certificate. At the time, I saw the job as a bit of a gap filler, until I worked out what I wanted to do with my life. Two decades later, that question still remains!

My first boss at St Marys was Professor Peter Openshaw. Time being what it is, he was the age I am now, when he first employed me. Perspectives change, while I now view the mid 40’s as a relatively youthful prime of life, I thought somewhat differently in my mid 20’s. I was working on a virus called RSV, which causes disease in babies and the elderly. When I started working on it, there was no vaccine, and it took until the late 2020s for one to be developed. One of the benefits of time passing is you get to see significant changes in your field – an insight that would have been lost on 20-year-old me.

One feature of the Mary’s medical school is that it worked in siloes. For those of you who haven’t had the pleasure/ experience of working at St Mary’s medical school, a quick intro into its somewhat dysfunctional architecture. The original building is three sides of a horseshoe, like a trapezium with the top cut off. This was then completed with an extra block (made of concrete) sometime in the 60s (an assumption I make due to the brutalist style). The newer block somehow squeezes in an extra floor, so has entirely different numbering, including the VD floor, which fans of childish humour enjoy. The final structure makes a square sided loop, with a big hollow in the middle, complete with a net to catch dead pigeons in various states of decay. But rather than being a free-flowing circuit of collaborative scientists, it historically was subdivided into little fiefdoms and woe-betide individuals crossing the iron curtain between them.

Good Times, Bad Times

I was indentured to the Respiratory Medicine department. There were three main supervisors, Peter (my boss), Seb Johnston and Jürgen Schwarze. Being mid-noughties the department was somewhat imbued with the spirit of ‘lad culture’ with lab cricket, massive multiplayer video games sessions, powerlifting, protein shakes and ‘the swim team’. But this was largely background noise, and it was a great time, I learnt (and did) a lot of immunology and got to work with a lovely group of people, with a shout out to my science bestie Dr (now professor) Cecilia Johansson who started at Mary’s two years after me. There were two timepoints seared into my schedule: 12:30 Mondays when the groups all came together and presented, and Thursday morning lab meetings in the third floor meeting room, including a memorable time when a chair collapsed underneath me, mid-discussion. I am extraordinarily grateful to Peter Openshaw for taking a punt on me (given I basically knew no immunology) and for continuing to support me. Thanks to his training and the collaborative environment, my immunology knowledge is much improved!

I then had a brief interlude when I moved labs to South London. I can only put this down to the sleep deprivation derived madness caused by having two children in three years. My most useful career tip from this brief period of exile from St Mary’s is to remember that the science world is really small. Luckily, I didn’t play out the fantasy of saying “screw you everyone I’m out of here”.

Start my group up

I say this was lucky, because little did I know at my time of exit, that I would find myself walking back down Praed Street, three years later, now as a lecturer. But don’t let my Paddington part two deceive you into thinking that I am less adventurous than your average Peruvian bear. On my return, I took up a lab on the fourth floor, one WHOLE floor up from where I had been previously AND in a different department.

My second spell began in 2011 on the 1^st April. Draw your own conclusions about the selection of start date. It’s worth noting that my PhD viva fell on the same somewhat inauspicious day of the year! And in the intervening 13 years since returning to Mary’s, my research group has really taken off, and there has been a succession of fabulous people who have worked with me in the intervening spell. I am completely indebted to Professor Robin Shattock with whom I have shared a lab for 15 years and who recruited me as a lecturer and latterly to Professor Wendy Barclay who took over as head of department in 2019, guiding it, us and me through the last five turbulent years.

The second time round as an ‘old-timer’, I have been more adventurous about where I spend my time in the building, not only spending time on floors three and four, but occasionally drifting down to two and very rarely (and bravely) up to five! One place I did spend a lot of time, was down in the basement, where the bar was. Sadly, the word ‘was’ doing some heavy lifting here, in the intervening time the bar had shut, and it had been turned into a lab. I have spent many hours in what was once the gent’s toilet; and they say scientific careers lack glamour.

Say Hello, Wave Goodbye

It is therefore with a sense of poignancy that I am approaching the final weeks at St Mary’s. There have been a lot of funny memories here, many of which are unrepeatable! Some of the printable highlights include a student pretending to be a spaceman by wearing a bin lid; signing a particularly earnest student up for a ladder safety course; persuading another of the team to autoclave a bottle of rotting media which stank out the whole lab for a week and the unmentionable blue bin. But the nostalgia is tempered by memories that are a product of working in a 100 year old building: ceilings that flood at the merest sight of rain, toilets that refuse to flush, a piece of chewing gum stubbornly clinging on to the urinal grill for the last 15 years, dead pigeons trapped in the netting designed to stop them flying into the air-con units (though this has led to the remarkable opportunity to watch a falcon eating its kill on said nets) and enough stained floor and ceiling tiles that one of the postdocs was able to sell a calendar’s filled with photos of them.

It is a building and site steeped with history. Every day I walk past the blue plaque commemorating Fleming’s discovery of penicillin; we regularly have seminars in a room named after Roger Banister (who broke the four minute mile, for those of you lacking in general knowledge as one of my students); and there are reminders of many of the other great scientists – storied or not who worked here. But in the end, change must come, and I am looking forward to moving to the South Kensington campus of Imperial. The good news for me is that this isn’t really a new workplace – as I did my PhD there even longer ago than I moved to St Mary’s. As they say, plus ca change, plus c’est la meme chose – the more it changes, the more it's the same thing.

My top 5 books on infections

 Did a fun project for a book blog called Shepherd. In which I got to talk about my 5 favourite books

https://shepherd.com/best-books/novels-and-nonfiction-books-about-infections-and-p 

Keeping track of a slippery customer

We are on the brink of something remarkable. The virus that I have been working on for 21 years (and that others have been studying for considerably longer) is about to have not one, but three vaccines. The virus is Respiratory Syncytial Virus (RSV), which is a cause of severe disease at both ends of life – putting both babies and the elderly into hospital. However, as we saw with COVID, getting a vaccine for a respiratory virus is not the end of the journey, merely the end of the beginning.

One of the major challenges with viruses is their tendency to mutate to escape the protective immune response from vaccines. This may be particularly problematic for another of the approaches being rolled out to prevent RSV – an antibody called Nirsevimab. Antibodies are proteins made by the immune system, they are able to bind other proteins with incredible specificity. In the case of viruses, the antibodies bind the surface proteins that viruses use to enter human cells. Nirsevimab targets an RSV protein called F (for Fusion) and has proved highly effective at reducing infection and severe disease.

The worry is that because Nirsevimab and the vaccines all target this RSV F protein, the virus might mutate to escape from being seen by the immune system. It is therefore important to keep a close eye on the virus to see if it is changing. This is where our latest paper Robust and sensitive amplicon-based whole-genome sequencing assay of respiratory syncytial virus subtype A and B comes in. Working with UKHSA (UK Health Security Agency), the government agency tasked with protecting the nation’s health, a new and improved method of sequencing RSV was developed. This is faster, cheaper and more reliable than the old method. The team sequenced over 1,000 different RSV isolates covering a 4 year period 2019-23. Importantly the approach is now in place ready for the rollout of the vaccines and antibodies, giving health authorities a fighting chance of keeping on top of this important cause of childhood disease.

Alliterative vaccines for influenza: DNA NA

Despite SARS-CoV-2 taking the limelight for the last 4 years, Influenza virus continues to be a significant threat to human health. It poses a number of threats to our health and wellbeing. These fall into three categories: seasonal, pandemic and zoonoses.

1.       Seasonal influenza. Lockdown type interventions (sometimes called NPI or non-pharmaceutical interventions) were highly effective at reducing the spread of not just SAR-CoV-2 (the virus that caused COVID) but other respiratory viruses too. The number of influenza virus infections went right down during 2020 and 2021. So much so that in fact one of the strains of influenza has disappeared. However, you can’t keep a good (bad) virus down and in the following winter (2022) flu had bounced back up to its usual levels causing illness, hospitalisation and death. Influenza virus is at its most serious at different times of the year depending upon where you live, but flu loves the winter – if you are in the southern hemisphere this means it peaks around June/ July, if you are in the Northern Hemisphere December is peak flu. These viruses change slowly over time, which is why there is a need for annual boosters.

2.       Pandemic influenza. There is a grinding low level of influenza disease year on year which causes a catalogue of low to middle grade misery. However, every so often (about once every 20 years) a completely new strain of influenza virus emerges infecting everyone. Not dissimilar to COVID a flu pandemic would cause immense disruption and death.

3.       Zoonotic influenza. We think of influenza as something that people get, but really it is an animal disease, particularly birds. The natural host of influenza is ducks, they spread it to chickens who spread it to pigs and people and the cycle continues. At the moment there is an unpleasant bird variant of influenza that has even made it to the icy shores of Antarctica causing penguins distress.

Vaccination takes the edge off some of these problems, and it is definitely worth getting vaccinated to protect yourself against the worst/ most severe disease. But the vaccines could be improved – giving you broader protection for longer. The huge breakthroughs with the RNA vaccines for COVID showed that other, newer platforms enable rapid responses to viral infections.

In our study Optimizing a linear ‘Doggybone’ DNA vaccine for influenza virus through the incorporation of DNA targeting sequences and neuraminidase antigen, we worked with a company called Touchlight Genetics who have a process for making DNA without all the bother of cells. Their Doggybone DNA (so called because of its shape) can be rapidly produced and in large amounts. This makes it a strong contender for future vaccine programs, especially against pandemic viruses. However, the Doggybone DNA vaccine platform needs a bit more work to be effective as a human vaccine, which is where our joint project came in.

We looked at two aspects to improve responses. The first was quite technical and involved tweaking the DNA sequence to allow more of it to get to the place it was needed (the nucleus). The second was looking at targeting a different part of the virus. Influenza makes two proteins on its surface, one that it uses to get into cells (Haemagglutinin or HA) and another that it uses to get out of them (Neuraminidase or NA). One thing to remember about the HA protein is that in spite of publishing papers about it for the last 15 years, I still cannot spell it – putting in too many or too few G’s, T’s or N’s. Most influenza vaccine research targets the HA protein, the idea being if you stop the virus before it ever gets into cells you can stop it in its tracks. However, targeting the NA protein has some advantages – it changes less than HA, so possibly you can increase the breadth of responses. This is helpful because the broader the anti-influenza response, the more protection you have when the virus changes its coat. We explored using the Doggybone DNA to make a vaccine that targeted influenza NA and showed that it could indeed protect against infection and disease.

Overall this work demonstrated that it is possible to further improve a DNA vaccine. By taking this marginal gains type of approach, it may be possible to develop influenza vaccines that cover all strains for all people.

Don’t worry – be happy

 In which I got to say Shit in Times Higher Education (first published there 2023)

The editor has allowed me 800 words to give you the secret to academic happiness, but I can sum it up in eight: stop giving a shit about every little thing. To be honest, it doesn’t even need the “about every little thing”. But I should probably expand a bit, and not least because I get paid by the word.

In case my head of department is reading this and I sound overly nihilistic, I need to provide some clarification. I am not saying “don’t try” and I am not saying you don’t have to work hard – whether we like it or not, academia isn’t a nine-to-five job. What I really mean is stop stressing about the things you cannot control – which, to be honest, is most things. I also mean loosen your attachment to the standard metrics of academic success – “high impact” papers, measures of esteem, fellowships of exclusive organisations. Most of these things have little or no relevance outside the ivory tower – as a fun way to test this, explain to a non-academic friend how you paid £8,490 for the privilege of someone else posting your research data online.

A more grown up way to put it is to have some perspective, but that way I don’t get to say shit in Times Higher Education.

An important point in the N.G.A.S. philosophy is that it applies predominantly to the higher levels of Maslow’s hierarchy of needs – those of self-esteem and self-actualisation. No amount of not giving a shit is going to help if you are underpaid, overworked and worrying where your next contract is coming from. If you are in this position, you have my utmost sympathy. But if you have survived that stage and are still feeling unfulfilled and miserable then read on.

Much of the current system equates academic happiness with academic success. But this can lead to chasing of endpoints for the sake of accolade rather than enjoyment of the thing itself. The goal should be a well-written paper that, through the effort of yourself and your team, pieces together a story addressing a research question that was important to you. The goal should not be getting it past a specific editor, who has a particular target audience in mind. One of the healthier developments in recent years has been the uptake of the Declaration on Research Assessment (DORA) and the move to recognise papers for their own merit, not just for where they are published.

Likewise with funding, write the best grant you possibly can, enjoy the process of thinking up new ideas, but accept that it may not be what the funders are looking for at that time and you might need to repackage for somewhere else.

And there are so many things that matter more than papers and grants. Strip away the stuff that is valued collectively by “the system” and focus on the stuff that matters to you. Be that teaching an enjoyable course with engaged students; widening participation in your field; answering a research question or finding the perfect bon mot for your writing. Academia sans merde gives you amazing opportunities to set your own path.

A corollary is to do things outside the academy that give you joy. If all you have in your life is your work, it is much easier for it to overwhelm you when things don’t go according to plan.

Not giving a shit doesn’t mean not caring about others. Another advantage of stepping away from externally defined success is that it is likely to reduce bad behaviour. The zero-sum model of perceived excellence, where only a select few PIs can win and everyone else loses, promotes toxicity. Focussing on actual excellence can be done with others, and everyone can win.

Hopefully, I have persuaded you of the case for caring less. But doing it isn’t as easy as it sounds. Letting go takes commitment. You need to work at it, especially in the face of the little siren voices that say you need more success to be happy.

A particular temptation is comparison. Never give in to this one. If there is one sure-fire way to be miserable in academia it is to compare yourself to other academics and their externally broadcast achievements. Bear in mind that those broadcasts are about achievements framed in defined (and quite artificial) terms, not about happiness or fulfilment. You can do better, by focussing on what matters to you and the consequences will be of far greater value.