Can research into viral reassortment reduce the transmission of Bunyaviruses?
An international team of scientists is investigating the reassortment rates of Bunyaviruses to compare differences between ticks, small and large vertebrates and humans.
Most people in the UK have never heard of Bunyaviruses or the diseases they cause, such as Rift Valley fever, Lassa fever and Crimean-Congo haemorrhagic fever (CCHF).
Transmitted by mosquitoes, rodents and ticks, Bunyaviruses feature on a list of nine diseases that the World Health Organisation (WHO) has highlighted as priorities for research and development. All nine diseases have the potential to cause a public health emergency, but we still know little about them and there are few effective treatments or vaccines for them.
Scientists at the University of Leeds are determined to change this. By working with scientists from the Los Alamos National Laboratory in the USA, UKHSA (formerly Public Health England, UK), Tajikistan and Turkey, they want to develop a better understanding of Bunyaviruses.
They are bringing together expertise in mathematics and virology to study CCHF, a disease on the WHO research priority list with fatality rates in hospitalised patients as high as 50 percent.
Why is CCHF so dangerous?
The CCHF virus is found throughout Eastern Europe, the Balkans, Russia, north-western China, central Asia, Africa, the Middle East, and the Indian subcontinent.
Initial symptoms of CCHF are headaches, high fever, back and joint pain and vomiting, followed by severe bruising, nosebleeds and uncontrolled bleeding.
A particular feature of the CCHF virus and other Bunyaviruses is that their genome is separated into three different segments, rather than a single one. This allows them to mutate through a mechanism called reassortment.
When host cells are infected with two different strains of the same Bunyavirus, each with three segments of RNA, the cell will contain a total of six different segments of viral RNA.
In this scenario, when the virus replicates, the new viral particles can contain any combination of these six different segments, potentially creating up to eight new viral strains, called ‘reassortants’, that can be radically different from the parental ones.
Bunyavirus expert, Dr John Barr, from the University of Leeds’ Faculty of Biological Sciences, explains:
“Reassortment can accelerate the mutation of Bunyaviruses. Rather than the gradual changes in viruses that small mutations can create, reassortment can make a big shift very quickly – with the potential to create strains that lead to more severe disease.”
What research into reassortment can tell us
The researchers will use data from in vitro experiments (experiments that involve infecting cells in a dish) to develop mathematical models of the intracellular life cycle and reassortment of Bunyaviruses.
They will then compare these models and experimental results with data from the field, based on samples from infected ticks, local and migratory birds, small and large vertebrates, and CCHF patients in Turkey and Tajikistan, to create a more detailed picture of how the virus mutates in different hosts.
Gaining new insights through maths
Dr Barr and his team will be conducting laboratory experiments in specialist facilities at the University of Leeds, using less dangerous forms of Bunyavirus.
They will co-infect cells with different strains, and use biological tests and microscopy to determine which new reassortants are created and how long they remain viable once they are outside the cell.
Professor Grant Lythe and Dr Martín López-García from the University’s School of Mathematics and Professor Carmen Molina-París from Los Alamos National Laboratory, will use the data sets to develop mathematical models that can determine the rate at which cells become infected, the rate of replication of the virus, the rate of reassortment and the rate at which viral particles can exit one cell to infect others.
Professor Molina-París, who is also a Visiting Professor at the University of Leeds, says:
“While the in vitro experiments show you what viral reassortants you get from certain viral inputs, the mathematical models help us to ‘see’ what is happening within the cells in different scenarios – what we call the intra-cellular replication dynamics of the virus. We have developed similar models for the Ebola virus and now we will apply these same techniques to Bunyaviruses.”
Looking for reassortment patterns in field data
A team from Los Alamos will be analysing field data from Turkey and Tajikistan.
They will use samples from ticks that carry the CCHF virus, small and large birds and animals (both wild and domesticated) that can be infected but show no symptoms, and hospitalised CCHF patients.
The researchers want to see whether any viral reassortment patterns they observe in the laboratory can also be found in the field.
“CCHF is a disease that affects humans but not animals, although vertebrates can be infected and act as viral reservoirs,” explains Professor Molina-París.
“We want to understand if the evolutionary dynamics of the virus – the way it replicates and creates new strains through reassortment – happens differently in these different hosts.”
This knowledge is an essential first step to develop novel antiviral therapies and assess the epidemic potential of the different strains of CCHF virus that are circulating in the world.
The research – funded through UK Research and Innovation and the National Institutes of Health in the USA – is due to start in April 2022.
Dr John Barr is a Programme Leader for Microbiology in the School of Molecular and Cellular Biology at the University of Leeds.
Professor Grant Lythe is a Professor of Applied Mathematics in the School of Mathematics at the University of Leeds.
Dr Martín López-García is an Associate Professor in the School of Mathematics at the University of Leeds.
Professor Carmen Molina-París, from Los Alamos National Laboratory, is a Visiting Professor in the School of Mathematics at the University of Leeds.
