FIP treatment - Infection and mutation of FCoV

I often find conflicting conclusions about this puzzling disease but I will keep updating and correcting this summary of FIP as I find more information or new data are made available.

First, I will summarise how FIP kills a cat, then I will try to clarify a few misconceptions about the disease.

The feline enteric coronavirus typically lives and replicates in the apical cells of the intestinal villi. Feline coronaviruses infect both domestic and wild cats, but are normally non-pathogenic or cause only mild disease. Enteric coronaviruses are usually kept in check by the beneficial gut microflora. If the beneficial and commensal microorganisms that work closely with the immune system in the gut are destroyed, the virus is able to replicate unchecked inside the enterocytes.

Stress is also linked to FIP morbidity. The cells that are able to neutralise FIPV before it infects monocytes/macrophages are destroyed when the cat suffers a stress episode. The amount of virus shed in faeces of cats that have been re-homed or placed in a shelter has been measured to increase by up to a millionfold, so this higher replication rate allows for a higher number of ‘mistakes’ in the translation and replication of viral proteins.

It’s possible that there are highly-mutagenic strains of FCoV, or that some mutations are more virulent. Genetics plays an important role and breeding two closely-related cats that are seemingly resistant to FIPV does not make the kittens resistant to the disease: inbreeding is a predisposing factor. The consensus seems to be that minimising stress and fomenting gut health reduces virus mutation.

Every so often, a mutation allows the FCoV to penetrate the cell membrane of macrophages in enteric tissues and use the cell’s ribosomes to make copies of itself. The cell then spills these virions into the bloodstream where they can infect and destroy other monocytes if they are not neutralised by passing T-cells.

While the virus is in the blood, the immune system can destroy it and the cat will not get sick (according to some estimates 80% of FIPV mutations never result in FIP.) However, if for any reason the thymus is damaged, the virus is able to penetrate the macrophage membrane and take control of these cells.

In a healthy cat, neutrophils are responsible for phagocytising pathogens and killing them with very potent toxins. They also produce proteins that are responsible for repairing different body tissues. These neutrophils are in turn eaten by the larger macrophages, which also express cytokines that tell neutrophils what to do and when to self-destruct. Neutrophils typically live 12 hours, until they receive an ‘order’ to self-destruct and are engulfed by the macrophages before their toxins can damage the cat.

This process is turned upside down when the FIPV invades a macrophage. The virus causes the macrophages to start sending the wrong chemical messages to the neutrophils (they produce neutrophil survival factors like TNF-α), telling them not to eat the pathogens in the blood and not to self destruct when they get old. This overproduction of neutrophil survival factors contributes to the development of granulomatous lesions typical of dry (non-effusive) FIP. Then two things happen: (1) the cat's body, sensing that there is ‘rubbish’ lying around, keeps producing neutrophils to phagocytise it; and (2) since neutrophils no longer receive orders to self-destruct, they go on living indefinitely until they come apart and spill their toxins and granules into the bloodstream. (When seen with a microscope, these are old, unhealthy neutrophils, different from the immature neutrophils produced when a cat is fighting a bacterial infection; also, both the neutrophils and the macrophages are empty, as they are no longer phagocytising. FIP macrophages are also more spongy than healthy ones.) It is for this reason that the seg count goes up in FIP, since mature (segmented) neutrophils are not marked for destruction and engulfed by macrophages.

It’s these toxins and granules inside the neutrophils that kill the cat. In effusive FIP, the blood vessel walls are so damaged that they leak protein-rich serum into body cavities. The cat will look thin but present abdominal, pleural or scrotal swelling, and will lose muscle mass as it’s starved of nutrients. Also, the granules can cause scar tissue chunks called granulomas. These are not tumours and are not operable (as an aid towards diagnosing FIP, these are neutrophilic granulomas.) The macrophages typically also stick to blood vessel walls causing vasculitis generally associated with effusive FIP.

It is believed that cats that present a limited cell-mediated immune response develop dry FIP, and those cats that fail to mount a cell-mediated response at all will develop wet FIP. Cats present different symptoms depending on where the inflammation is taking place (eyes, brain, gut, kidneys, liver, etc.)

It has been stated that more cats are killed by FIP titres than by FIP itself. Virtually all cats in catteries and shelters shed FCoV at some time in their lives and have FCoV antibodies. This number is lower in households with only one or two cats but because the virus can live for some time in the environment, any cat can be infected with the benevolent strain at any time, and iatrogenic infection is possible (although probably uncommon). Cats with fulminant effusive FIP often have no antibodies, and some cats with high FCoV titres never develop FIP. I want to stress that no tests available today are able to detect the virulent FIPV, and there is no such thing as an FIP test so no cat should be euthanised because it has tested ‘positive for FIP.’

It’s possible that finding the virus in some tissues like the membrana nictitans makes FIP more likely. A quantitative test for messenger RNA seems to indicate that the virus is replicating in monocytes/macrophages, which would exclude the non-pathogenic FCoV (which replicates in gut cells), but according to all the information that I can find no single test can diagnose FIP.

The main concern of cat owners is contagion from a cat that has died of FIP. Although it seems that FIPV can occasionally be shed in faeces, this mutated form doesn't seem to be able to infect other cats. Most researchers agree that the mutations take place inside the cat and several pathogenic mutants are possible. So a cat can be infected with FCoV, but it needs to mutate the virus individually —and have a malfunctioning immune system— in order to get FIP.

People also understandably seek a vaccine that protects their cat from this horrific disease. The Primucell vaccine is recommended by the manufacturer for cats that have no antibodies to FCoV, but the vaccine is given to kittens after 16 weeks of age, by which time most kittens have already been exposed to the virus. Also, the modified live virus can get past the cells of the immune system and infect the cat. Most vets agree that vaccination against FIP is not recommended.

The other problem is that antibodies to FCoV may actually help the virus infect the cat’s cells. This has not been proven in vivo but I will mention two mechanisms by which this could indeed be the case. First, it’s possible that antibodies act as opsonins that facilitate virus adsorption to the cell membrane. Another possibility is that antibodies internalise or bind to plasma membrane viral proteins making the infected macrophages invisible to passing thymocytes that could neutralise the infected cells.

FIP treatments

Corticosteroids

Immunosuppressants like Prednisolone are widely used in FIP to reduce inflammation although there are no studies that prove its benefits in the long term. On the contrary, corticosteroids have the effect of destroying the cells of the immune system that can neutralise the virus in the bloodstream, so a cat whose thymus has been damaged by Prednisolone, Dexametasone, etc., doesn't have a chance to fight off the infection.

Interferon

Interferons are molecules that the cells of the immune system use to send signals to other cells or to themselves. These molecules (called cytokines) act as text messages between leukocytes that tell other cells what to do, when to come to a site of infection, when to phagocytise a pathogen, etc.

In some forms of FIP interferon levels actually go up, so feline interferon omega is not likely to benefit these cats. Human interferon will be seen by the cat's immune system as an antigen and neutralised by antibodies.

Polyprenyl Immunostimulant

PI is used off-label for cats with mild forms of FIP, but according to the research I've found it's not proven to work with cats suffering from effusive or severe forms of dry FIP. More research will show if this can indeed benefit terminally ill cats.

Proteinase inhibitors

This is being touted as the Holy Grail of FIP research, and it has worked in all cats inoculated with an FIP mutant in the lab and apparently some naturally infected cats as well. You can read Dr. Niels Pedersen's preliminary report here.

At the risk of sounding like a doomsayer, I think the emergence of antibiotic-resistant bacteria should serve as a cautionary tale for those researchers advocating the use of antiviral drugs.

Viruses are essentially chunks of Ribonucleic or Deoxyribonucleic Acid (RNA or DNA) usually protected by a protein coat. Unlike bacteria, they cannot function autonomously and need to make use of a cell's ribosomes to make copies of themselves. Being much smaller and simpler than bacteria, viruses are able to replicate very quickly. Inevitably a number of mutations will arise every so often.and the risks of potentially resistant strains are very high, especially and notoriously in the case of coronaviruses. This is particularly true in the case of chronic infections that need prolonged drug exposure.

The paper states that the mutants that arise as a result of antiviral pressure have a lower replicating capacity and do not cause lethal disease, but this was only tested in a murine model (mouse hepatitis virus). It's possible that the mutants in the MHV model are easily neutralised by the immune system because it has not been suppressed by the virus. In the case of FIP, the damage to lymphocytes and particularly to cytotoxic CD8+ T-cells could allow for even more virulent 'hot strains' with the potential to spread through feline populations.

Luckily FIP is still a relatively rare disease in domestic cats, so this treatment might indeed work because the use of antivirals will not be widespread, but I still feel that this breakthrough fails to address the root cause of FIP, which is a malfunctioning immune system.

In my opinion, we are still a long way from winning the arms race against viruses and only the cat's lymphocytes through the TCR repertoire can match the replicating capacity of FIPV.