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== Protecting kittens through breastmilk ==
== Protecting kittens through breastmilk ==


Kittens born to mother carrying FECV are protected from infection during their first weeks of life (until weaning food). Dr. Addie [http://www.dr-addie.com/] advocates early weaning and segregation of kittens from their mother before they contaminate each (5 to 6 weeks). Kittens outside contamination, but are deprived of contact with their mother during their 2 months of life (an important educative time).
Kittens born from mother carrying FECV are protected from infection during their first weeks of life (until weaning food). Dr. Addie [http://www.dr-addie.com/] advocates early weaning and segregation of kittens from their mother before they contaminate each (5 to 6 weeks). Kittens outside contamination, but are deprived of contact with their mother during their 2 months of life (an important educative time).


The initial protection of the kittens is very effective. We have to reflect about the different possible ways to do it.
The initial protection of the kittens is very effective. We have to reflect about the different possible ways to do it.

Revision as of 05:31, 8 May 2009

Feline coronavirus FCoV

This is an RNA virus that can infect cats. This virus has 2 forms:

1/ An enteric one (intestinal) called FECV (Feline Enteric Coronavirus)

2/ And a form that can cause the feline infectious peritonitis FIPV (Feline infectious peritonitis virus).

They are part of the coronavirus group 1, like the porcine gastroenteritis swine coronavirus (TGEV), the canine coronavirus (CCOV) and some human coronavirus.

The cat coronavirosis

The digestive form FECV

FECV virus is responsible for an infection of the gastrointestinal epithelial cells of the cat (the intestinal lining cells) See also enterocytes, brush border, microvilli, villi ...): intestinal infection with few signs, it is most often chronic. The virus is then excreted in the feces of the animal (healthy carrier). This port can be demonstrated by rectal sampling (swab) and detection by PCR: Polylmerase Chain Reaction or "PCR".

Cats living in groups are contaminating each other during visits to the litter tray. Some cats are resistant to the virus and have no infection (no carrying digestive). Others will be carriers of FECV some time. They may heal spontaneously, but acquired immunity is short, they are going to infect an other time during a few weeks if they are living in a group with persistent excretory (healthy carriers). Some cats never heal and excretory remain permanently.

Passage from the FECV form to the FIPV one

Random errors replication in the enterocyte, sometimes the virus can mutate from FECV to FIPV.

More the cat group is big (n cats) and more the epidemiological risk of mutation (E) is high:

E = (n ²)-n

A house hosting 2 cats has a mutation risk = 2. If 4 kittens born in this house, the risk growth up from 2 to 34.

It's easy to understand, cats are permanently infected with a larger number of different strains of virus (as different from cats), visiting litter tray.

In the natural state cats are solitary animals, they don't sharing their areas (hunting area, rest area, area of defecation ...). Often domestic cats live in a group, it's a hight epidemiological risk situation.

After this mutation, the FCoV acquires a tropism for the macrophages [1] (see also: Immune cells, white blood cell, leucocyte monocyte, dendritic cells, mononuclear cells, antigen presenting cell ...) while losing the intestinal tropism.

The feline infectious peritonitis and the FIPV virus

See also the special article about feline infectious peritonitis

In a cat group, the overcrowding and the risk of mutation (from FECV to FIPV) are risk factors for the development of cases of feline infectious peritonitis '(FIP)' . However, the FIP will mainly develop in cats whose immunity is low (younger kittens, old cats, immunosuppression due to viral - FIV (Feline immunodeficiency virus) and / or FeLV Feline leukemia virus) - stress including stress of separation and adoption).

Infection of macrophages by FIPV is responsible for a fatal granulomatous vasculitis, the FIP (see granuloma).

Therefore, FIP can occur in 2 factors are meeting: (virus mutation) AND (cat field)

  • Mutation of the virus: virological factor related to the number of replication ...
  • Field of cats related to its age, its genetics, its stress level, which determines the immune status and thus its ability (or not) to contain the infection at a low level.


There are 2 clinical forms of FIP '(feline infectious peritonitis )':

  1. An effusive form with effusion peritoneal fluid (= ascites), pleural and pericardial,
  2. And a dry form.

Usually, the outcome is fatal, except for a few reported cases of healing with the feline omega interferon treatment.

Molecular aspects of the virus fusion to the host cell

The 2 forms of FCoV, the enteric one (FECV) and the FIP one (FIPV) have both from 2 different serotypes (with different antigens that cause different antibodies production of: serotype).


The FCoV serotype I (also called Type I) is most frequent: 80% of infections are due to type I FECV that could mutate to FIPV type I. Serotype I FCover Cultures are not easy, so studies about this serotype are few.


The FCoV serotype II (also called type II) are less frequent: FECV type II that can mutate to FIPV type II. FCoV type II is a recombinant virus type I with spikes genes (S protein) replacement from FCoV by the canine enteric coronavirus (CCOV)spikes. [2] The type II cultures are easier, so we have many studies about this type II (though less common).

Model: "data about FCoV type II"

Virus fusion

FCoV is an RNA viruses that is included in the coronaviruses group 1. Coronaviruses are covered with several types of proteins "S proteins" (or E2) forming a crown of Spike to the virus surface. 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 him to a membrane receptor of the host cell: the Feline Amino peptidase N (fAPN). [3] · [4] · [5]

The viral receptor: aminopeptidase N (APN )

fAPN (feline), hAPN (human) and pAPN (porcine) differ in some areas of N-glycosylation, that can explain:

  • 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 form receptor (pAPN)
  • The pig coronavirus can bind to the porcine APN (pAPN) but not the human form receptor (hAPN).

At the cellular level this facts can explain why the glycosylation level of enterocytes APN is important for the binding of virus to the receptor. [6] · [7]

About viral spikes

The FECV spikes have a high affinity for enterocytes fAPN , while the mutant FIPV spikes have a high affinity for the macrophages ones.

During the viral replication cycle, spikes proteins have a maturation in the host cell golgi with a high mannose glycosylation.

This spike manno-glycosylation stage is indispensable for the acquisition of coronavirus infesting power. [8] · [9]

Data about FCoV type I

The receptor?

In 2007, it is well established that serotype I do not work with the FCoV fapn receptor. The FCoV type I receptor still is unknown.[10]


News about CoV receptor

  • The human CoV SARS binds to the Angiotensin-converting enzyme ACE II. The ACE II is also called 'L-SIGN'.
  • Coronaviruses bind to macrophages via the "DC-SIGN". Sign-DC = Dendritic cell (see also hepatitis C, hepatitis B, HIV ...)

ACE and DC-SIGN are two trans-membrane receptors (mannose receptors) which can bind 'the plant lectins C-type mannose binding'. DC-SIGN and ACE serve as retrovirus receptors.[11]


  • 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, wich is suggesting a common phylogenetic origin between these molecules.
  • Some advanced studies have shown a high homology between the Aminopeptidase N and the Angiotensin-converting enzyme. [12]


  • It is likely that the unknown FCoV serotype I receptor is also of this receptor family that acting with the mannose binding lectins.

Role of mucus and glycocalix - Interactions between viruses and sialic acid

Sialic acid is a component of the complex sugar glycocalix, ie mucus protecting the gastrointestinal mucosa (but also respiratory one...). Sialic acid is an important facilitating fusion factor of any viruses to the host cell. This is very well detailed for the flu.

Extensive data also show that processes using sialic acid are directly involved in the interaction with receptors lectins.[13]


About swine enteric coronavirus (group 1), it has been demonstrated that fusion to the enterocyte was through binding to the APN in the presence of sialic acid, the 2 elements are necessary. [14] · [15] · [16]

About Felin coronavirus infections, it seems that the infection is sialic acid dependent.[17] · [18]

Inhibition of the fusion: some studies (in vitro)

To inhibit the fusion of the virus to the cell, several solutions are possible:

  1. modify glycosylation level of the viral spikes,
  2. Change the level of glycosylation of fAPN,
  3. Compete with the spikes, with molecules that will bind to fapn (occupation of the binding site),
  4. Inhibit the binding depends on the sialic acid mucus.


  • Experimentally the binding of FIPV (spike) in macrophages (fapn) is strongly inhibited by mannan(s)( mannose complex sugar - see also, glycan, manno-oligosaccharide, MOS oligosaccharide): that compete with the fapn. With mannose, the inhibition is less than with Mannan-oligosaccharides.
  • Some Molecules can inhibit glycosylation of spikes (monensin, tunicamycin ...) reduce or cancel the virus infesting power (action in the Golgi. The same is true for mannanases and mannosidase enzymes that cut mannose out of the spikes.
  • The competition with spikes by other molecules having an affinity for fapn '(common sugar recognition process)' cancel or reduce the power of infesting CoV:


- Mannan binding Lectin:

  1. Allium agglutinins
  2. Urtica dioica agglutinins
  3. Pradamycine A .../...
    • humoral lectin
  1. Ficoline
  2. Collectine .../...

-Manno-Oligosaccharides (MOS) : source: yeast


- sialic acid :

Ewperimental sialic acid inhibition can decrease the avian and human coronavirus infectivity.[20]

Protecting kittens through breastmilk

Kittens born from mother carrying FECV are protected from infection during their first weeks of life (until weaning food). Dr. Addie [1] advocates early weaning and segregation of kittens from their mother before they contaminate each (5 to 6 weeks). Kittens outside contamination, but are deprived of contact with their mother during their 2 months of life (an important educative time).

The initial protection of the kittens is very effective. We have to reflect about the different possible ways to do it.

Antibodies

It is widely accepted that passive protection is borne by the immunoglobulins nursery (antibodies) provided by the colostrum and the milk from the mother.


Several questions arise:

  1. If this protection is only supported by maternal antibodies so why these antibodies do not protect the mother herself?
  2. The kittens born to a mother's blood group B are removed from their mother for 24 hours (to avoid the Hemolytic disease of the newborn) and thus have no systemic passage of maternal antibodies. Why is it not described FCoV infection in these kittens more often than others?

Colostrum

Other molecules fromcolostrum and cat milk, could also bear this coverage:

  • Lactoferrin,
  • Lactoperoxidase,
  • Lysozyme,
  • Rich Proline polypeptide – PRP,
  • alpha-lactalbumine,
  • .../...

Lactoferrin has many properties that make it a very good candidate for this anti-coronavirus activity:

  1. As CoV group I, it binds to APN [21]
  2. As the SARS CoV, it binds to enzymes convert angiotensin[22]
  3. It binds to DC-SIGN of macrophage,[23]
  4. The Lactoferrin anti-viral activity is sialic acid dependent.


Other components

The colostrum and breast milk also contains:

  1. Many oligosaccharides (glycan) responsible for anti-viral,[24]
  2. Many maternal immune cells,
  3. Many cytokines (interferon ...); whose role by oro-mucosal route seems very important.[25] · [26] · [27]
  4. sialic acid: during lactation, it appears that neutralizing oligo-saccharides binding sialic acid decreases when it binds increasingly to glycoproteins[28].

(The APN is a glycoprotein). The anti-viral effect of lactoferrin is increased by the removal of sialic acid.[29]

  1. Mannan binding lectins. [30]
  2. .../...


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.[31] The spikes of CoV could then not be bound.
  • Factors breastmilk may inhibit the synthesis of fANP by enterocytes, as already described with fructose or sucrose.[32] · [33] · [34]

Links

[2] Dr ADDIE website focused research about FIP

[3] Coronavirus "Patric" website

[4] Coronavirus Site général

[5] Coronavirus site général

[6] Coronavirus Pictures

References

  1. ^ Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein
  2. ^ Feline coronavirus type II strains 79-1683 and 79-1146 originate from a double recombination between feline coronavirus type I and canine coronavirus.
  3. ^ Feline aminopeptidase N is a receptor for all group I coronaviruses
  4. ^ Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I
  5. ^ Virus-receptor interactions in the enteric tract. Virus-receptor interactions
  6. ^ Molecular determinants of species specificity in the coronavirus receptor aminopeptidase N (CD13): influence of N-linked glycosylation.
  7. ^ Identification of sugar residues involved in the binding of TGEV to porcine brush border membranes
  8. ^ Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein.
  9. ^ Utilization of DC-SIGN for entry of feline coronaviruses into host cells.
  10. ^ Type I feline coronavirus spike glycoprotein fails to recognize aminopeptidase N as a functional receptor on feline cell lines
  11. ^ The C type lectins DC-SIGN and L-SIGN: receptors for viral glycoproteins.
  12. ^ Analyse structurale du site actif de trois métallopeptidases à zinc: Endopeptidase Neutre-24. II, Aminopeptidase N et Enzyme de Conversion de l'Angiotensine
  13. ^ Sialic acid-specific lectins: occurrence, specificity and function.
  14. ^ Binding of transmissible gastroenteritis coronavirus to cell surface sialoglycoproteins.
  15. ^ Identification of sugar residues involved in the binding of TGEV to porcine brush border membranes.
  16. ^ Binding of transmissible gastroenteritis coronavirus to brush border membrane sialoglycoproteins.
  17. ^ Association between faecal shedding of feline coronavirus and serum alpha1-acid glycoprotein sialylation.
  18. ^ Serum alpha1-acid glycoprotein (AGP) concentration in non-symptomatic cats with feline coronavirus (FCoV) infection.
  19. ^ Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle.
  20. ^ Infection of the tracheal epithelium by infectious bronchitis virus is sialic acid dependent.
  21. ^ Recognition of lactoferrin and aminopeptidase M-modified lactoferrin by the liver: involvement of the remnant receptor.
  22. ^ Lactoferricin-related peptides with inhibitory effects on ACE-dependent vasoconstriction.
  23. ^ Lactoferrin prevents dendritic cell-mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN--gp120 interaction.
  24. ^ Human milk glycans protect infants against enteric pathogens.
  25. ^ Use of oromucosally administered interferon-alpha in the prevention and treatment of animal diseases.
  26. ^ Oromucosal cytokine therapy: mechanism(s) of action.
  27. ^ Oromucosal interferon therapy: relationship between antiviral activity and viral load.
  28. ^ Distribution of bovine milk sialoglycoconjugates during lactation.
  29. ^ Involvement of bovine lactoferrin metal saturation, sialic acid and protein fragments in the inhibition of rotavirus infection.
  30. ^ Changes in the mannan binding lectin (MBL) concentration in human milk during lactation.
  31. ^ Localization and biosynthesis of aminopeptidase N in pig fetal small intestine.
  32. ^ Folding of intestinal brush border enzymes. Evidence that high-mannose glycosylation is an essential early event.
  33. ^ Morphological and functional changes in the enterocyte induced by fructose.
  34. ^ Post-translational suppression of expression of intestinal brush border enzymes by fructose.
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