Oxford Science Blog

Samantha Vanderslott and Seilesh Kadambari

By Dr Samantha Vanderslott, Oxford Martin School and Dr Seilesh Kadambari, Department of Paediatrics

Why is this important to us?

We have been struck by how COVID-19 has affected the health and wellbeing of ethnic minority groups disproportionately. Individuals from these communities are more likely to have severe disease requiring intensive care admission and sadly succumb to infection than those from a white ethnic background. This is independent of age, gender or socioeconomic factors. However, vaccine uptake has been low in certain communities and for lots of different reasons. These include specific concerns about vaccine safety, increased exposure to misinformation, reduced access to vaccines and historical distrust with institutions. Asylum seekers have cited negative experiences with authorities, and some don’t trust public health messaging related to vaccines. Central government often use one-way messaging, which will sometimes miss these groups. Promoting vaccination through celebrity adverts, videos via social media and community champions may also not reach disaffected communities who feel marginalised during the pandemic. We encourage a two-way dialogue in the hope that these groups can trust us with providing evidence-based answers to queries and enable informed decision making before getting a vaccine.

What are we doing?

We found approximately 200 community organisations online that provide community, religious or social support to individuals and groups across the UK. We approached these organisations to invite us to any online meetings being held during the lockdown in order to provide information about the vaccine, answer questions and encourage dialogue. Our intention has been not to overwhelm individuals with information and so we do not use slides or overly scientific language. The majority of our meetings are therefore spent listening to concerns or questions, addressing these directly and encouraging two-way conversation.  

We have spoken to organisations that support asylum seekers, refugees, interfaith groups and elderly ethnic minority citizens. Concerns have ranged from the risk of deportation by registering for a vaccine, addressing misinformation that has circulated in specific communities and discussing a range of vaccine safety concerns. 

Who is involved?

This initiative is conducted by Dr Seilesh Kadambari and Dr Samantha Vanderslott. We are based at Oxford Vaccine Group and use information and materials from the Vaccine Knowledge Project.

The Vaccine Knowledge Project has also worked with the British Islamic Medical Association to develop FAQs about vaccines and vaccine ingredients translated into over 100 different languages and available on the website. This resource has been shared through these online conversations and their communities. The calls are facilitated by the organisations that we have reached out to. We have benefited from having a medic able to address safety issues and health conditions and a researcher able to address vaccine policies and misinformation.

What works for us?

Most importantly, this work has highlighted the importance of connecting with individuals and groups directly. We ensure that every opportunity is taken to answer questions and that individuals can make an evidence-based decision on whether to receive a vaccine. The meetings, facilitated by community leaders, are held at convenient times for different organisations. For example, in the afternoon for an organisation supporting elderly women of South Asian background, in the evening after work for a group supporting asylum seekers and on a weekend before Ramadan for Muslim organisations.  It has been deeply humbling and thoroughly enjoyable work. Our aim has been to provide individuals with sufficient confidence to receive a vaccine and therefore ensure protection against a pandemic that has exacerbated disparities in these vulnerable groups.

More information

For information and materials on vaccination, check out the Vaccine Knowledge Project.

There are also plenty of other examples of good practice.

Fruit fly

By Dr Ellie Bath, Department of Zoology

Mating changes female behaviour across a wide range of animals, with these changes induced by components of the male ejaculate, such as sperm and seminal fluid proteins. However, males can vary significantly in their ejaculates, due to factors such as age, mating history, or feeding status. This male variation may therefore lead to variation in the strength of responses males can stimulate in females.

Using the fruit fly, Drosophila melanogaster, we tested whether age, mating history, and feeding status shape an important, but understudied, post-mating response – increased female-female aggression.

Two females fighting over foodTwo females fighting over food

Image 1: Two female fruit flies are standing on a food cap (which contains food that they eat and lay eggs in). This is where the majority of fighting happens – you can see the flies have their legs touching, so they are probably fencing in this image. Each fly is marked with a different colour of paint to aid identification.

We found that females mated to old males fought less than females mated to young males. Females mated to old, sexually active males fought even less than those mated to males who were merely old, but there was no effect of male starvation status on mating-induced female aggression.

Male condition can therefore influence how females interact with each other – who you mate with changes your interactions with members of the same sex! 

Image 2: This figure shows the setup we used for contests between females, which consisted of a circular arena with a food cap set into the middle. This food cap contained regular fly food medium, with a drop of yeast paste in the middle to act as a valuable, restricted resource.

Contest arena setupContest arena setup

Could this happen in other species?

We know that other species (including humans!) have proteins in the seminal fluid that males transfer to females during sex. Various of these proteins have effects on female physiology and behaviour, but no one knows if these affect aggression (in humans or any other species).

We also know that male age (in flies and humans) results in reduced fertility and can have serious effects on their offspring. Although it is a long leap from flies to humans, could who you mate with influence your interactions with other females?

Many reproductive molecules and important bodily functions are conserved across the animal kingdom from flies to humans, so it is possible that what we found in flies here might be hinting to a common phenomenon across the tree of life. We need more studies to understand if this is the case!

Read the full paper, 'Male condition influences female post mating aggression and feeding in Drosophila' in Functional Ecology.

 

Oxygen bubbles

By Professor Jane McKeating, Nuffield Department of Clinical Medicine

Oxygen is essential to all life forms, even viruses. 

Oxygen is fundamental to all cells, impacting key functions such as metabolism and growth. Our cellular response to oxygen levels is tightly regulated and one important pathway is controlled by the Hypoxia Inducible Factors (HIFs), that activate certain genes under low oxygen conditions (hypoxia) to promote cell survival. Drugs that activate HIF are currently in use to treat anaemia caused by kidney disease.

The novel coronavirus SARS-CoV-2 needs no introduction and literally stopped the world in 2020, with more than 2 million fatalities to date. A defining feature of severe COVID-19 disease is low oxygen levels throughout the body, which may lead to organ failure and death. A cure for this virus is urgently needed.

Dr Peter Wing and Dr Tom Keeley, working in the laboratories of Prof Jane McKeating, Prof Peter Ratcliffe and Dr Tammie Bishop in the Nuffield Department of Clinical Medicine, discovered that a low oxygen environment supressed SARS-CoV-2 entry into cells that line the lungs and reduced viral propagation and shedding.

Importantly, drugs that activate HIF such as Roxadustat had a similar effect on the virus. This study provides the first evidence for repurposing HIF mimetics that could reduce SARS-CoV-2 transmission and disease development. The oxygen dependency of this virus is a new vulnerability that we could exploit. 

Research continues to expand our understanding of the interplay between oxygen sensing and COVID-19 and is published in Cell Reports

Comparing a healthy aorta with what it looks like in the event of an aneurysm

By Talitha Smith, Communications Officer, Department of Physiology Anatomy and Genetics (DPAG)

An abdominal aortic aneurysm (AAA) is a bulging of the aorta, the body’s main blood vessel, which runs from the heart down through the chest and stomach. Prevalence of AAA in the population is high, up to nearly 13% depending on age group, particularly for men aged 65 and over. An AAA can get bigger over time and rupture, causing life-threatening bleeding. There is a high mortality rate of around 80% in patients with ruptured AAA; only dropping to around 50% when patients undergo surgery.  

Comparing a healthy aorta with what it looks like in the event of an aneurysmComparing a healthy aorta with what it looks like in the event of an aneurysm
While clinicians can monitor the beginnings of AAA, a rupture can occur suddenly without warning. Currently, the only available intervention involves a high-risk surgical procedure, which is only undertaken if there is a real danger of rupture. There are no pharmacological treatment options because the underlying causes of AAA are not fully understood.   

Scientists know that in some patients there is a genetic predisposition to AAA, and large genomic studies have identified that mutations in a large protein called LRP1 predispose people to aortic aneurysm, as well as other major vascular diseases. However, the mechanism responsible for how these mutated genes cause the disease has so far been unknown.  

Vascular smooth muscle cell differentiation is essential to the development of healthy blood vessels. The smooth muscle cells of the aorta play a crucial role in maintaining its stability and protecting it against disease. In their healthy contractile state, they provide strength and produce the elastin proteins to withstand forces and assist with pumping blood around the body. In disease, damage to the lining of the aorta causes accumulation of fat and allows immune cells to infiltrate vessel walls. In response, the vessel attempts to repair itself and the smooth muscle cells try to make more smooth muscle. However, in doing so, the cells start to de-differentiate and become less contractile.

They undergo proliferation, presumably with good intentions to try and make more smooth muscle, but actually it makes the problem worse. 

According to Associate Professor of Cardiovascular Development and Regeneration Nicola Smart: 'They undergo proliferation, presumably with good intentions to try and make more smooth muscle, but actually it makes the problem worse. In doing so, they also break down the elastic layers that keep the vessels stable. These layers are supposed to hold the whole vessel together, keep it tight and keep it strong, and it all breaks apart.' 

But why do the smooth muscle cells react in this way? Professor Smart's research group has found that a small protein called Thymosin b4 (Tb4) is working alongside the larger LRP1 protein to determine how many 'growth factor receptors' are sent to the cell's surface to respond to disease. If Tb4 is absent, then instead of being destroyed, too many receptors are recycled back to the cell's surface, which makes the smooth muscle cells hyper-sensitive and in essence overreact.

Professor Smart’s team then compared their results with AAA samples from the Oxford Abdominal Aortic Aneurysm study. The OxAAA team surgically repair aneurysms in human patients, removing diseased tissue from the lining of the abdomen in the process. Through examining these samples, the Smart group were able to confirm that Tb4 and LRP1 interact in both healthy and diseased patient vessels. Consequently, their study sheds light on a key regulatory step in AAA and Tb4 has been identified as a promising new drug target to potentially treat the disease. 

More details can be found in The Journal of Clinical Investigation, (which includes a full list of contributors, including the first author, DPhil student Sonali Munshaw).

Clock

By Professor Jane McKeating, Nuffield Department of Medicine

Our lives are so often dictated by time - it seems like we are not the only ones.

Most living things are aware of the time of day and respond through endogenous biological rhythms, with an approximate cycle of 24 hours. This “circadian clock” controls a range of biological processes including hormone secretion, metabolic cycling and immune protection against pathogens. More recently, the circadian clock has been shown to influence viral infection by altering the host pathways essential for their replication.

Circadian rhythms are everywhere and so are viruses - the interaction between them is both incredibly fascinating and perhaps unsurprising. 

Hepatitis B virus (HBV) is a globally important pathogen, with over 270 million individuals infected and at risk of developing liver disease or cancer. A cure for this virus is urgently needed. Dr Xiaodong Zhuang, researcher in the  McKeating Group laboratory, recently showed that circadian rhythms influence HBV replication. This research found that the key circadian transcription factor (BMAL1) binds the HBV genome. This ‘intimate’ virus-host interaction promotes viral infection in cells and in animals models, providing exciting avenues for the discovery of new anti-viral drugs. Interesting questions remain to be answered as to whether HBV infection can 'reset' the clock and how this may impact liver cancer development.

Being in synchrony with your body might mean being in synchrony with your viruses.

The circadian clock is thought to be around 2.5 billion years old, tracing back to the cyanobacteria that released vast amounts of oxygen during the Great Oxidation Event. Interestingly, many of the elements of our oxygen sensing systems are homologous to those we use for sensing time, and there is growing evidence of an interplay between the circadian and hypoxia signalling pathways.

Work from the same lab by Dr Peter Wing and colleagues recently found that this ancient oxygen sensing system promotes HBV replication through the well-defined hypoxia induced factors. Has HBV co-evolved to use these two ancient pathways (circadian clock and oxygen sensing) to infect the liver? It seems plausible that such interactions will be found for many other viruses.

To find out more about circadian rhythms and HBV, read the full paper published in Nature Communications.