Feline coronavirus

# Overview
Feline Coronavirus (FCoV) is a positive stranded RNA virus that is infectious to cats worldwide. This virus is part of the coronavirus group 1, which includes the porcine gastroenteritis swine coronavirus (TGEV), the canine coronavirus (CCOV) and human coronavirus 229E. It has two different forms; the FECV (Feline Enteric Coronavirus) that infects the intestines and the FIPV (Feline Infectious Peritonitis Virus) that causes the disease Feline infectious peritonitis.
Feline Coronavirus is typically shed in feces by health cats and transmitted by the fecal-oral route to other cats.  In environments with multiple cats, the transmission rate is much higher compared to single cat environments. The virus is insignificant until mutations cause the virus to be transformed from FECV to FIPV. FIPV causes Feline infectious peritonitis for which there is no known cure; treatment is generally symptomatic and palliative only.

# Virology

## Feline enteric coronavirus (FECV)
Feline enteric coronavirus is responsible for an infection of the mature gastrointestinal epithelial cells (see also enterocytes, brush border, microvilli, villi). This intestinal infection has few outward signs, and is usually chronic. The virus is excreted in the feces of the healthy carrier, and can be detected by Polymerase Chain Reaction or "PCR" of feces or by PCR testing of rectal samples.
Cats living in groups can contaminate each other with different strains of the virus during visits to a communal litter tray. Some cats are resistant to the virus and can avoid infection or even becoming carriers, while others may become FECV carriers. Carriers may heal spontaneously, but acquired immunity may be short and they may go on to reinfect, usually within a few weeks, if they are living in a group with healthy, but persistent excretory carriers. Some cats never heal and the excretory phase remains permanently.

## Feline infectious peritonitis virus (FIPV)
The virus becomes feline infectious peritonitis virus when random errors occur in the virus infecting an enterocyte causing the virus to mutate from FECV to FIPV. FIPV causes a lethal, uncurable disease Feline Infectious Peritonitis (FIP). In one case study, a female cat diagnosed with FIP survived 26 months from the date of definitive diagnosis (Fall 2009).
In a large group of cats (n) the epidemiological risk of mutation (E) is higher and expressed theoretically as E = (n 2)-n. A house hosting 2 cats therefore has risk of mutation E = 2. When 4 kittens (6 cats in total) are born into this house, the risk increases exponentially from 2 to 30.
In their pre-domestication natural state cats are solitary animals and do not share space (hunting areas, rest areas,  defecation sites, etc.). Domestic cats living in a group therefore have a much higher epidemiological risk of mutation. After this mutation, the FCoV acquires a tropism for macrophages   (see also: Immune cells, leucocyte, monocyte, dendritic cells, mononuclear cell, antigen-presenting cell) while losing intestinal tropism.

## Feline infectious peritonitis and FIPV
In a group of cats, overcrowding increases the risk of mutation and conversion from FECV to FIPV which constitutes a major risk factor for the development of feline infectious peritonitis(FIP) cases. FIP has been shown to develop in cats whose immunity is low; such as younger kittens, old cats, immunosuppression due to viral  FIV (Feline immunodeficiency virus) and / or FeLV Feline leukemia virus  and stress, including the stress of separation and adoption.
Infection of macrophages by FIPV is responsible for development of a fatal granulomatous vasculitis, or FIP (see granuloma).
Development of FIP depends on two factors: virus mutation and low immunity where virus mutation depends on the rate of mutation of FECV to FIPV and the immune status depends on the age, the genetic pool and the stress level. High immune status will be more effective at slowing down the virus.

# Molecular Biology of Feline Coronavirus
Two forms of feline coronavirus are found in nature: enteric (FECV) and FIP (FIPV). There are also two different serotypes are found that have with different antigens that produce unique antibodies. FCoV serotype I (also called type I) is the most frequent. Type I, that can be defined as 'FECV that could mutate to FIPV type I', is responsible for 80% of the infections. Typically, serotype I FCoV cultures are difficult to perform, with few resulting studies. FCoV serotype II (also called type II) is less frequent and is described as 'FECV type II that can mutate to FIPV type II.' FCoV type II is a recombinant virus type I with spike genes (S protein) replacement from FCoV by the canine enteric coronavirus (CCOV) spikes. The type II cultures are generally easier to perform, which has resulted in an imbalance of experiments performed with many studies about type II (even though it is a far less common form).

## Molecular model of FCoV type II

### Virus fusion
Coronaviruses are covered with several types of "S proteins" (or E2) forming a crown of protein spikes on the surface of the virus. Coronaviruses take their name from the observation of this crown by electron microscopy. These spikes of Cov (group 1 and serotype II) are responsible for the infection power of the virus by binding the virus particle to a membrane receptor of the host cell - the Feline Amino peptidase N (fAPN).

### The viral receptor: aminopeptidase N (APN)
fAPN (feline), hAPN (human) and pAPN (porcine) differ in some areas of N-glycosylation. All strains of the coronavirus study group 1 (feline, porcine and human) can bind to the feline aminopeptidase N fapn but the human coronavirus can bind to the human APN (HAPN) but not to the porcine type receptor (pAPN) and the pig coronavirus can bind to the porcine APN (pAPN) but not the human type receptor (hAPN). At the cellular level the glycosylation level of enterocytes APN is important for the binding of virus to the receptor.

### Viral spikes
The FECV spikes have a high affinity for enterocytes fAPN, while the mutant FIPV spikes have a high affinity for the macrophages fAPN. During the viral replication cycle, spikes proteins mature in the host cell Golgi complex with a high mannose glycosylation. This spike manno-glycosylation stage is vital for the acquisition of coronavirus virility.

## Molecular Model of FCoV type I

### The receptor
In 2007, it was well established that serotype I did not work with the FCoV fAPN receptor. The FCoV type I receptor still is unknown.

### CoV receptor
The human CoV SARS binds to the Angiotensin-converting enzyme ACE II. The ACE II is also called 'L-SIGN' (liver/lymph node-specific intracellular adhesion molecules-3 grabbing non-integrin). Coronaviruses bind to macrophages via the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) which is a trans-membrane protein encoded in humans by the CD209 gene.. ACE and DC-SIGN are two trans-membrane retrovirus receptors (mannose receptors) which can bind 'the plant lectins C-type mannose binding '.
Aminopeptidase N has the same ability to interact with plant lectins C-type mannose-binding and also serves as a receptor for a retrovirus. Angiotensin-converting enzyme ACE, aminopetidase A and aminopeptidase N have cascading actions in the renin-angiotensin-aldosterone system, which suggests a common phylogenetic origin between these molecules. Some advanced studies have shown a high homology between the Aminopeptidase N and the Angiotensin-converting enzyme. It is more than likely that the unknown FCoV serotype I receptor is also a member of this receptor family and acts with mannose binding lectins.

## Interactions between the viruses and sialic acid
Sialic acid is a component of the complex sugar glycocalix, which is the mucus protecting the gastrointestinal and respiratory mucosa. It is an important facilitating fusion factor of any viruses to its host cell which has been very well studied for flu.
Extensive data also shows that processes using sialic acid are directly involved in the interaction with the receptor's lectins. It has also been demonstrated that swine enteric coronavirus (group 1) fusion to the enterocyte is accomplished via binding to the APN in the presence of the sialic acid. Felin coronavirus infections are therefore sialic acid dependant.

# Effects of breast milk on kittens
Kittens born from mothers carrying FECV are protected from infection during their first weeks of life until weaned by maternal antibodies. It is recommended that the kittens are weaned early and segregated from their mother before they infect each other (at about 5 to 6 weeks). Kittens with no outside contamination and that are deprived of contact with their mother during their first 2 months of life (an important immunological period) may be protected.

## Antibodies
It is widely accepted that passive protection is passed on to kittens by immunoglobulins nursery (antibodies) provided by colostrum and the mother's milk. However, several questions arise:
- If this protection is only supported by maternal antibodies, why don't these antibodies protect the mother herself?
- If the kittens born to a mother's blood group B are removed from their mother for 24 hours (to avoid Hemolytic disease of the newborn) and thus have no systemic passage of maternal antibodies, why don't we see FCoV infection in these kittens more often than others?

## Colostrum
Other molecules from colostrum and cat milk, could also bear this coverage: Lactoferrin, Lactoperoxidase, Lysozyme, Rich Proline polypeptide  PRP and alpha-lactalbumine. Lactoferrin has many properties that make it a very good candidate for this anti-coronavirus activity:
- As CoV group I, it binds to APN 
- As the SARS CoV, it binds to enzymes convert angiotensin
- It also binds to DC-SIGN of macrophage,
- The Lactoferrin anti-viral activity is sialic acid dependent.
The structures of the polypeptide chain and carbohydrate moieties of bovine lactoferrin (bLF) are well established. bLF consists of a 689-amino acid polypeptide chain to which complex and high-mannose-type glycans are linked (Pierce et al., 1991)

## Other components
The colostrum and breast milk also contain:
- Many oligosaccharides (glycan) which are known for their anti-viral properties which is thought to be primarily due to their inhibition of pathogen binding to host cell ligands.
- Many maternal immune cells
- Many cytokines (interferon ...); whose role by oro-mucosal route seems very important
- Sialic acid: during lactation, neutralizing oligo-saccharides binding sialic acid decreases when it binds increasingly to glycoproteins. (The APN is a glycoprotein). The anti-viral effect of lactoferrin is increased by the removal of sialic acid.
- Mannan binding lectins.

## Other protective factors
Other assumptions may help to explain this resistance to FCoV infections by kittens. In the first weeks of life, APN could be immature because highly manno-glycosylated. The spikes of CoV could then not be bound. Factors in breastmilk may inhibit the synthesis of fANP by enterocytes, as already described with fructose or sucrose.