Views from the London School of Hygiene & Tropical Medicine

Cytomegalovirus in human embryonic lung revealed using immunofluorescence

A viral spanner in the works

By Carolyn NielsenCarolyn Nielsen, PhD student: essay shortlisted for Max Perutz Science Writing Award.

It sounds like a bad science fiction plot, but sometimes it would be easier if everyone was identical.

I’m interested in how vaccines activate our immune systems and how this then works in the real world to protect us from dangerous infections. The problem is that not everyone’s immune cells respond in exactly the same way, meaning vaccines often work better in some people than in others. This can be at a local level, such as between your colleagues at work, or on a grander scale with differences between whole geographical regions. For example we know that BCG, the vaccine for tuberculosis, is less effective in sub-Saharan Africa than here in the UK.

This is partially due to genetics – the genes for key molecules on immune cells have a huge amount of variation – while some is due to other factors you can’t blame on your parents, such as ageing. Environmental influences, like nutrition or infection, can also affect your immune system. A perfect example of nature versus nurture.

My research at the London School of Hygiene & Tropical Medicine focuses on how one common virus, cytomegalovirus, contributes to this puzzle. Cytomegalovirus is a type of herpes virus that has co-evolved with humans for thousands of years. Our immune systems generally control it, but we can never entirely get rid of the virus. This constant pressure on your immune cells over time is like the cellular version of going grey – some types of cell in infected people become more mature and less responsive. This effect is similar to what is seen during normal ageing, but is unparalleled by any other infection.

In developing countries, including in sub-Saharan Africa, almost everyone is infected with cytomegalovirus. The prevalence varies in Europe or the USA but generally 30-50% of young adults have cytomegalovirus, not 100%. Cytomegalovirus could therefore be one of reasons why vaccines don’t work as well in the developing world. Unfortunately, this is difficult to investigate as there are no uninfected people in these countries to participate in studies for comparison.

My project therefore looks at comparing immune cells from infected and uninfected people in the UK. I wanted to find out if there are any differences in responses when the cells are stimulated with vaccines, using whooping cough as an example. This involves mixing immune cells from previously vaccinated people with the whooping cough bacteria, then looking at how the cells react. Successful vaccination against whooping cough gives your body a sneak preview of killed whooping cough bacteria, triggering the build-up of an arsenal of memory immune cells that can fight infection fast if you get exposed. Mixing your immune cells and whooping cough bacteria in the lab can give us an idea how well you might respond and be protected.

As immune cells activate, different molecules are sent to their surface which we can detect using fluorescent tags that stick only to these specific molecules. The number of cells that get labelled with the fluorescent tags tells us about how well that person has responded. This can be measured using a technique called flow cytometry, which uses lasers to calculate what percentage of cells have been marked with each tag. The lasers allow us to count hundreds of thousands of cells per minute- a much faster and more accurate method than staring down a microscope!

So far, we’ve been able to show that people infected with cytomegalovirus have less powerful responses by a type of immune cell called natural killer cells. These cells don’t have memory themselves, but they can respond very quickly to signals sent from other cells, like T cells, that do have memory and can recognise whooping cough bacteria. We’re now trying to understand how cytomegalovirus has changed the natural killer cells to undermine the vaccine response.

It’s not yet clear how large an impact these natural killer cell changes will have on the overall efficacy of a vaccine. We also don’t know how important it is if you become infected with cytomegalovirus before or after vaccination. Additionally, since cytomegalovirus causes similar immune system changes to healthy, normal ageing, it is likely the relationship between infection and age is complicated. Interestingly, we have seen that natural killer cells in 10-year olds with cytomegalovirus infections in The Gambia (West Africa) have already undergone changes you wouldn’t expect to see until late adulthood in uninfected people.

If future work builds on this and demonstrates there is a link between cytomegalovirus infection and poor vaccine efficacy, then the value of this research lies in helping to identify weak spots in vaccination programmes. Whether it’s development of better vaccines with adjuvants (like an espresso for the immune system), or simply showing who needs the help of a booster jab, understanding why some people’s immune systems respond half-heartedly to vaccines is crucial for guiding effective vaccination policies.

Carolyn Nielsen, a PhD student on a Medical Research Council (MRC) studentship at the London School of Hygiene & Tropical Medicine, was shortlisted for the MRC’s annual Max Perutz Science Writing Award. Carolyn’s essay, “A Viral Spanner in the Works”, focuses on the possible link between cytomegalovirus infection and poor vaccine efficacy.

Carolyn’s essay, as well as those of the winner and other shortlisted entrants, can be viewed on the MRC website.

Image: Cytomegalovirus in human embryonic lung revealed using immunofluorescence.
Credit: CDC/ Dr. Craig Lyerla

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