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Recent advances in the pathogenesis and diagnosis of feline corona virus infections.

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Feline infectious peritonitis (FIP) is caused by the feline coronavirus (FCoV). FCoV are widespread in feline populations and usually infect enterocytes. During viral replication, viral variants called “quasispecies” are generated. Some of these “mutant” variants are able to replicate within macrophages and they spread throughout the body within these cells. Conversely “non-mutated” FCoVs can infect circulating monocytes but are thought to be unable to replicate within these cells. The precise mutation responsible for this different cell tropism has not yet been identified. Nevertheless, some polymorphic sequences of the viral genome which are able to influence the host responses have been identified. This aspect is extremely important in the basis of the pathogenesis of FIP since ultimately the development of disease depends on the type of immune response of the host: a strong cell-mediated immunity could protect FCoV-infected cats from FIP , whilst a weak cell-mediated immunity predisposes to FIP especially in the presence of hyperactivation of humoral immunity that induces an overproduction of anti-FCoV antibodies. In turn this induces the formation and deposition of immune complexes that determine a type II hypersensitivity reaction responsible for the vasculitis that characterizes the disease. Innate immunity is also thought to be involved in the pathogenesis of FIP . The acute phase protein alpha1-acid glycoprotein (AGP) dramatically increases and is hyposialylated in cats with FIP , while hypesialylated AGP transiently increases in clinically healthy cats when the number of shedders in the cattery increases. This raised the hypothesis that AGP and AGP sialylation could play a role in protecting from or predisposing FCoV infected cats to FIP . Recently this hypothesis has been supported by the finding that hyposialylated AGP depresses the phagocytic activity of feline phagocytes. Diagnosis Based on the pathogenesis described above, it is obvious that the simple detection of FCoV genome or of anti-FCoV antibodies is not useful for the diagnosis of FIP . FCov positive cats could actually be infected by “non mutated” viral variants and conversely, cats with FIP could have low antibody titers or low copies of viral genome when deposition of immune complexes occurs. Conversely, the detection of changes consistent with FCoV-induce tissue damage or with anti-FCoV responses could be diagnostic when FIP is clinically suspected. Specifically, the following tests can be used (ranked in terms of diagnostic relevance): - Histology: is considered the gold standard test and currently is the only method that confirms FIP , especially if followed by immunohistochemistry (IHC) to detect FCoVs in the lesions. IHC on tru cut or FNA biopsies, however, has a low sensitivity. - Analysis of the effusions, when present. The effusion is yellowish, sticky, contains fibrin clots and has a high specific gravity and a high protein content. This latter finding is responsible for the positive Rivalta test, for the electrophoretic profile found in effusion (increased alpha2 and gamma-globulin) and for the granular background detectable on cytological examination of the effusions (other cytological findings are: non degenerated neutrophils, macrophages/mesothelial cells, lymphocytes). If needed, immunocytochemistry or immunofluorescence can be used to detect FCoVs within the macrophages detected cytologically. Conversely, PCR on the effusions can provide both false positive and false negative results, due to the kinetics of FCoV infection described above. - Serum protein electrophoresis: is one of the main diagnostic findings for FIP . It is characterized by increased alpha 2 globulins and by a polyclonal gammopathy - Serum AGP concentration. AGP increases in several inflammatory conditions, including FIP . However, increased of serum AGP are usually marked (higher than 1.5 mg/mL). - Other clinico-pathological findings reflect the inflammatory status associated with the infection (e.g. normocytic normochromic non regenerative anemia, lymphopenia and neutrophilia) or the presence of tissue damage, which is variable according to the organ(s) affected (e.g. increased creatinine/urea and/or increased hepatic enzymes, etc…) None of the above tests however, is sufficient on it’s own, to confirm the diagnosis of FIP . The diagnosis should be based on the pretest probability of disease, which in turn depends on a combination of history, clinical findings and laboratory abnormalities. To date it is not possible to predict the probability of disease in clinically healthy FCoV infected animals. Future studies should establish the possibility of using as biomarkers of resistance/susceptibility the quantitative and qualitative changes of molecules previously described to be potentially involved in FCoV-host interactions. Bibliografia 1. Addie D. D., Paltrinieri S., Pedersen N. C.: Reccommendations from workshops of the second international feline coronavirus/feline infectious peritonitis symposium. J. Feline Med. Surg. 6; 125-130, 2004. 2. Addie D, Belák S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lloret A, Lutz H, Marsilio F, Pennisi MG, Radford AD, Thiry E, Truyen U, Horzinek MC.:Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med. Surg. 11; 594-604, 2009. 3. Paltrinieri S., Giordano A., Tranquillo V., Guazzetti S.: Critical assessment of the diagnostic value of feline α1- acid glycoprotein for feline infectious peritonitis using likelihood ratios approach. J. Vet. Diagn. Invest. 29; 266-272, 2007. 4. Pedersen N.C.: A review of feline infectious peritonitis virus infection: 1963 – 2008. J. Feline Med. Surg. 11, 225-258, 2009. 5. Rossi G., Cornaro C., Battilani M., Pocacqua V., Paltrinieri S.: Production of IFN -γ in feline whole blood after incubation with potential T-cell epitopes of the nucleocapsid protein of feline coronavirus. Vet. Microbiol. 150; 248–256, 2011. 6. Ritz S., Egberink H., Hartmann K.: Effect of feline interferon-omega on the survival time and quality of life of cats with feline infectious peritonitis. J. Vet. Intern. Med. 21; 1193-1197, 2007. 7. Ishida T, Shibanai A., Tanaka S., Uchida K., Mochizuki M.:“Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis. J Feline Med. Surg. 6; 107-109, 2004. 8. Legendre A.M., Bartges J.W.: Effect of Polyprenyl Immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis. J. Feline Med. Surg. 11; 624-626, 2009.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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