A headstrong feline virus

The Feline ParvoVirus (FPV) attacks cells in the digestive tract and the precursor cells of bone marrow in cats. It triggers feline panleukopenia, a disease which generally leads to few symptoms in healthy, adult cats but which can lead to developmental problems in the cerebellum of kittens infected just before or just after birth.  However, during the feline parvovirus outbreak in 2013, vets reported very unusual nervous symptoms in adult cats infected by FPV. They asked the autopsy department of the University of Liège to investigate. What were the conclusions of this investigation? It is not impossible that the virus has evolved and become capable of reactivating the cell cycle (at least its initial phases) in the neurons, a mechanism which they need to multiply. This is an observation which could change our perception of the parvoviruses in general and raises questions as to the use of this type of virus for therapeutic ends, particularly in the fight against cancer.

Hiding in the shadows, invisible to the naked eye, viruses are everywhere. Thankfully, not all are dangerous, but all have the same objective: to infect a body which will enable them to multiply. Indeed, in contrast to bacteria, viruses are incapable of multiplying by themselves. They need to defeat the cells of another organism in order to use their finely-tuned machinery to replicate their genome. 

The parvovirus family includes a certain number of viruses which use animals or humans to multiply. Among them, is the feline parvovirus, or FPV. As its name indicates, it attacks felines, in our countries more specifically the domestic cat. It triggers a disease known as feline panleukopenia. ‘FPV infects dividing cells, particularly cells in the digestive tract and the precursor cells to white cells in bone marrow’, explains Mutien Garigliany, from the animal pathology department (FARAH - Faculty of Veterinary Medicine) at the University of Liège. ‘This virus generally provokes few symptoms in healthy adult cats.  But it reduces the white cell count, which can be dangerous for more fragile cats who will find it harder to defend themselves against other infections’, continues the researcher. Moreover, in kittens with many dividing cells, FPV attacks the nerve cells, principally in the cerebellum. ‘We can thus observe nervous symptoms in young kittens following infection. Traditionally, however, this is not seen in adults, whose neurons are no longer dividing’, specifies Mutien Garigliany.

A unique mutation in this strain of FPV

Feline panleucopaenia is a very common disease which can be well controlled through vaccination. But, as with intestinal flu in humans, for example, there are annual changes in its incidence, and there are regular outbreaks of parvovirus. In 2013, an otherwise normal feline panleukopenia epidemic drew the attention of vets in the field. ‘They were seeing a number of adult cats presenting nervous symptoms following infection, which is extremely unusual in cats of this age’,  states the scientist. ‘They therefore asked us to check whether FPV had infected the nervous tissues of these cats’. The researchers used PFV virus markers to highlight the tissues in which the virus was multiplying in those cats presenting nervous symptoms. Their analyses confirmed the presence of FPV in the cerebral neurons of these cats. ‘This was really surprising because parvoviruses need to infect dividing cells, which is not the case of these neurons’ continues the vet. ‘We therefore envisaged different hypotheses which we investigated with colleagues at ULg and ULB’. Initially, the scientists wanted to check whether this parvovirus had a different genome to the standard strain responsible for feline panleukopenia. ‘It is a virus with a relatively stable DNA, but one which evolves nonetheless. We developed new sequencing techniques to amplify all the viruses present in the cerebral tissues of the cats analysed. This enabled us to reveal a unique mutation in this strain of the FPV virus’, states Mutien Garigliany. This mutation is not present in any other virus of this type in the world. ‘We also checked whether these nervous symptoms could be connected to co-infection with FPV and another virus, but in most of the cases, there was no co-infection. This enabled us to conclude that the symptoms were probably indeed due to the presence of FPV’, continues the researcher. Following this observation, it would be interesting to isolate this virus which carries a unique mutation and to study it in greater detail, or to insert this mutation in a classic strain of the FPV virus and see how it behaves in vitro. ‘This could be, for example, the subject of a doctoral thesis for one of the teams involved in this study’, indicates Mutien Garigliany. 

Neurons which reactivate a cycle of cell division

What is FPV doing in tissues where the cells are no longer dividing? To find an answer to this question, the researchers started from the theory that these cells had perhaps reactivated the cycle of cell division. ‘And they do so either by themselves or are driven by the virus’, specifies Mutien Garigliany. ‘Professor Luc Poncelet from ULB used a p27 marker of cell ‘rest’ and was able to observe that this marker had disappeared in neurons infected by FPV’, explains the scientist. ‘The neurons therefore effectively re-enter, at least in the initial phases of the cell division cycle, which enables the replication of the FPV’. At this stage, the researchers do not know whether this is caused by the virus or not. ‘In order to multiply, this virus, which consists of DNA and a capsid, needs to use the machinery of a dividing cell’, recalls Mutien Garigliany. It is therefore not impossible that the virus has evolved and can now reactivate this machinery in certain cells, in this case, the neurons. ‘The mutation that we have identified in this strain of the virus affects a protein whose role in controlling the cell cycle has been established for other parvoviruses. We therefore suggest, although we cannot demonstrate it at this point, that a cause and effect exists between this mutation and the acquisition of the neuronal tropism that we have highlighted’, specifies the researcher.

Parvovirus and the fight against cancer: proceed with care!

This theory, which remains to be verified, may be vitally important for other research into parvoviruses. Scientists are studying the effect of using certain parvoviruses to fight cancer. ‘Given the tropism of this virus for cells which are rapidly dividing, cancerous cells are a dream territory for the virus which, as it multiplies, kills these cells’, continues the vet. 

But caution is required because the frontier between activation of the cell cycle and the destruction of cancer cells remains permeable. Recent results from Mutien Garigliany et al.’s study, published in the BMC Veterinary Research (1), are a good example of this. If parvoviruses evolve and acquire the capacity to reactivate cell division, they could potentially cause more harm than good, by attacking healthy tissues, such as the central nervous system, in addition to the tumour. ‘A well-known virus which presents this ability to push cells to divide is the papillomavirus, which is responsible for cervical cancer(2)’, indicates the scientist. Things are, therefore, not as straightforward as they may appear and extreme caution should be taken in terms of using the virus as a therapeutic tool. This study is interesting for at least two reasons: it provides insight into unusual cases of feline panleukopenia which were reported during the 2013 outbreak and it contributes towards improving knowledge of the interaction between parvoviruses and the cells they infect.

(1) Mutien Garigliany · Gautier Gilliaux · Sandra Jolly · Tomas Casanova · Calixte Bayrou · Kris Gommeren · Thomas Fett · Axel Mauroy · Etienne Lévy · Dominique Cassart · Dominique Peeters · Luc Poncelet · Daniel Desmecht. Feline panleukopenia virus in cerebral neurons of young and adult cats. BMC Veterinary Research. 12/2016; 12(1). DOI: 10.1186/s12917-016-0657-0 

(2) On this topic, read  The origins of cervical cancer