Architectural Antagonism by an Acute Arbovirus

“For many years, if not from the time of the introduction of the Merino sheep into the Colony, there has been prevalent amongst the flocks a disease known as fever. This disease is most prevalent during the summer months, and is very much worse in wet seasons.”

That was a quote from the Report of the Cattle and Sheep Diseases Commission for 1876, which referred to outbreaks of a deadly sheep disease in the country that would later become South Africa.

What’s remarkable, is that even after all this time, we don’t completely understand how this disease comes about. But a new piece of the puzzle has been found by researchers working at the CVR and across Europe and in doing so, they seem to have uncovered some fascinating new biology. 

…to find out more read the paper (OA) in PNAS here, read on at the blog, or listen to the podcast below.

A blue tongue

Before the late 19^th century, this disease had not been noted before but only appeared following the importation of European sheep breeds into southern Africa. In these animals an often fatal, devastating illness would develop, characterised by difficulty breathing, sore lesions across the body and the appearance of a swollen, blue tongue. This disease would be known as malarial catarrhal fever but later referred to as, simply, ‘bluetongue’.

Over the last century we now know that bluetongue is spread by midges, a kind of blood-sucking insect and is caused by a virus, known as bluetongue virus – or BTV- which is similar to the human rotaviruses, which cause serious gastrointestinal disease in people.

BTV has been found right across the world, in the Americas, Australia, Asia and Europe, where it also infects cattle and goats and is the cause of serious economic damages. In 2007, the UK reported its first ever outbreak of the disease, which arrived from mainland Europe. A changing climate is allowing midges – and BTV – unprecedented access to new areas of the globe making future outbreaks more likely.

While a vaccine exists, protecting against BTV this way is challenging due to the great antigenic diversity that exists. Nearly 30 different kinds, or serotypes, of BTV have been documented and that immunisation against one will not confer protection against any other. So in order to have complete immunity against BTV, we must find a way to vaccinate against all serotypes. No such vaccine exists currently but there are ones against individual important serotypes, which includes BTV-8, the virus causing trouble across Western Europe this summer. 

How BTV cause the disease?

What’s really amazing is that we don’t fully understand how BTV infects and causes disease in animals. One of the reasons is the difficulty in doing experiments in the natural host species of BTV, which are sheep.

Working with collaborators across Europe, in Scotland, Spain and Italy, the Palmarini group looked at the very early stages of BTV infection in sheep and found that the virus can infect and disable, a special cell found in the lymph nodes.

These cells – known as follicular dendritic cells (FDCs)–  have a critical role in lymph node architecture and B cell development, which might be one way that this virus escapes the sheep immune response. FDCs , which have little relation to classical dendritic cells (they originate from the stem cells that make immune cells in the blood), are thought to come from structural cells, like fibroblasts and endothelial cells (the cells that line your blood vessels). Of note, BTV will infect, replicate and kill endothelial cells, which in part explains the deadly, systemic disease known as bluetongue.

Using experimental infection of sheep with BTV serotype 8, Melzi et al., really focused on what was happening in the first few hours of infection, following inoculation of the virus into the skin, to simulate a bite with an infected midge. Using antibodies that bound to BTV proteins and to sheep cell proteins, they tracked virus spread into and across the lymph nodes where they hunted for what kinds of cells BTV got into. What was striking from the start was that BTV appeared to cause a disruption of lymph node architecture within the first few days of infection. The Palmarini group found that BTV could infect a range of lymph node cells but it was the FDCs that stood out due to their importance in lymph node function and maintaining its organisation.

Virus-induced damage to FDCs impairs the ability of the sheep to mount an antibody response, effectively setting up a short-term dampening of the immune response to everything, not just BTV. Lymph nodes are an incredibly important part of your immune system, where much of the adaptive immune response is generated. This includes your antibody and cellular immunity, which comes from B cells and T cells, respectively. Stopping them working as they should would endow the virus with a larger window of time to replicate, cause disease, and presumably be transmitted. Importantly, Melzi et al., infected sheep with a weakened or attenuated strain of BTV and saw that this immunosuppression wasn’t as strong as it would have been if infected with the original BTV strain.

Would other arboviruses do this?

The group believe that a similar virus-induced short dampening of the immune response could be happening in many other arboviruses that infect humans and other animals. Arboviruses are spread by biting insects and arthropods: mosquitoes, sandflies, midges and ticks. They have to get in, replicate very fast and to high levels – often causing an acute disease, so as to be passed on to another biting insect or tick. But their first encounter with a vertebrate will always be our skin. Melzi et al., would think that Crimean-Congo haemorrhagic fever virus (CCHFV) would be a likely candidate to do this because, like BTV, it also infects and replicates in endothelial cells and may share the ability to infect FDCs. 

In conclusion, this work documents a new kind of trick that a virus uses to escape the immune response of its host. Of note is the fact that this is caused by an arbovirus, a group of viruses that are have a continuous relevance to human and animal health. The study by Melzi et al., reinforces the importance of doing virus experiments in relevant animal systems and in the worth of carrying out basic science in veterinary diseases.

By Dr Connor Bamford, @cggbamford

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The CVR has a broad, collaborative programme on arboviruses as part of its ‘Emerging & zoonotic viral infections’ theme. In particular, the CVR investigates their molecular virology, virus-host interactions, vaccine development and vector biology of human and animal viruses across the different programme member labs of Alain Kohl, Steve Sinkins, Emilie Pondeville, Margus Varjak, the bunyavirus group and Massimo Palmarini. This strategy allows us to be prepared for future, often unpredictable, problems with arboviruses, but also work on ongoing issues.