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		Visions on the Future of Veterinary Virology Feline Infectious Peritonitis

		Potassium Homeostasis During Exercise Mini-review: Species-specific Primary Cell Cultures



		· Introduction · Virologist's perspective · FCoV carrier state · From the FCoV carrier state to FIP · Laboratory tests - are they useful? · References
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A virologist's perspective

Fig. 2 Electron micrograph of coronavirus particles. The name of this RNA virus family is derived from the name of the halo seen around the sun during an eclipse, the 'corona solis'. It refers to the fringe of petal-shaped spikes ('peplomers') radiating from the viron membrane. The peplomers carry epitopes, which induce neutralizing antibodies and provide protection against coronaviral disease, for example in pigs (transmissible gastroenteritis) and chickens (infectious bronchitis), but are at the base of the 'early death' phenomenon in cats.

Coronaviruses (genus Coronavirus, order Nidovirales) are common pathogens found in mammals (causing a form of 'common cold' in man, transmissible gastroenteritis in swine, diarrhoea in cattle and other conditions) and birds (giving rise to infectious bronchitis in chickens and bluecomb disease in turkeys). They are enveloped viruses, with an RNA genome about 30 kilobase in length, making theirs the largest of all RNA genomes. It is generally accepted that one out of 10,000 nucleotides is changed in any round of RNA genome replication. Consequently, myriads of copying errors can be expected: since the coronaviral genome holds about 30,000 nucleotides, one would differ from the next at least at one site. Thus, no two coronavirus particles are genomically identical - a notion that has led to the so-called 'quasispecies' concept.

Fig. 3 The quasispecies concept in viruses. The 'sequence space', indicated by the cube, represents the theoretically possible nucleotide variations in a replicating genome. A faithfully replicating genome - like that of a vertebrate - would occupy a point-like niche in sequence space, a hypothetical viral genome with unlimited degrees of freedom (all variants allowed and infectious) would fill the entire sequence space. Due to their poor replication fidelity, with 1:10,000 to 1:100,000 base substitutions per site, RNA viruses occupy a cloud-like niche in sequence space. This is the stuff of viral evolution: during transmission the virus goes through a population bottleneck and expands to a new 'quasispecies cloud' in the new host.

Viruses evolve more than a million times faster than cellular microorganisms, and one wonders how they can maintain their identities as pathogens over any evolutionarily significant period of time. As the Nobel laureate Manfred Eigen [3] exclaimed: "Why didn't they mutate out of existence?" The answer to this question is, of course, that individual viruses do not count biologically but rather a cloud of variants expanding around a 'consensus' sequence.

Although generally associated with acute, self-limiting enteric and respiratory infections, coronaviruses can also establish persistent infections. In vivo these have mostly been studied using mouse hepatitis virus as a model; suckling rodents may develop a chronic demyelinating disease not unlike multiple sclerosis in man, with viral replication in the central nervous system. From such animals, virus was isolated as late as one year after inoculation. Only a few studies have addressed the role of viral persistence during natural coronavirus infection, and FIP is now the most prominent example.

Feline coronaviruses cause mild enteric infections in almost all catteries in Western Europe and America (for a review see [5]). The low-virulence 'enteric' FCoVs and the disease-causing FIPVs are genetically closely related [6], and we think that the latter are virulence variants of the former, which arise in individual FCoV-infected hosts [12,15]. This means that no two cases of FIP are caused by identical viruses and that horizontal transmission, that is cat-to-cat transfer, is the exception rather than the rule.

On the basis of in vitro neutralization tests FCoVs can be allocated to one of the two serotypes mentioned above. Type I is prevalent in Europe, is found in most fatal cases of FIP, but is the least studied because of its reluctance to grow in culture. The type II FCoVs are more common in other parts of the world (e.g. Japan) and are a showcase of viral evolution. They arise from RNA recombination events during which genetic information from the canine coronavirus is incorporated into FCoV type I genomes [9,15].

Fig. 4 Genomic organization of and recombination between carnivore coronaviruses. The boxes represent the genes responsible for the 'structural' proteins building the virus particle, such as the 'peplomers' (see legend to Fig. 2) or spikes (S), two membrane proteins (E and M) and the nucleocapsid protein (N), which wraps the genome. POL stands for polymerase, and also the genes 3 and 7 code for non-structural proteins; mutations in the 3c gene have been found in coronavirus infected cats that developed FIP. The uppermost graph symbolizes the genome of a canine coronavirus, the lowest that of a feline coronavirus. Recombinants between both have been found in the field, and the varying cross-over sites indicate that this event occurs regularly.