Investigation of the virulence factor, antiviral agents, and host genetic susceptibility of feline infections peritonitis
Date Issued
2014
Date
2014
Author(s)
Hsieh, Li-En
Abstract
Feline infectious peritonitis (FIP) is an immune mediated highly lethal disease in all domestic and non-domestic Felidae. The causative pathogen of FIP is feline coronavirus (FCoV), which belongs to the Alphacoronavirus in the family Coronaviridae. The infection of FCoV is distributed widely around the world, including Taiwan. Most of the infection is asymptomatic and only mild enteritis could be observed in some kittens. However, there are about 5-12% seropositive cats will develop FIP. Once the clinical signs appeared, diseased cats usually died within one month. Hence, FIP is one of the most important diseases in cats. As a disease with nearly 100% of mortality, no preventive vaccine and effective therapeutic agents are currently available for FIP. Several questions regarding the virus and its related disease remain to be answered.
According to the outcome of infection, FCoV could be further categorized into two biotypes: feline enteric coronavirus (FECV), which leads to the enteric infection and is widely distributed in cat populations especially in multicat environment, and feline infectious peritonitis virus (FIPV), which induces the highly lethal FIP. In addition, these two biotypes of FCoV showed a difference in infection kinetics in vitro and in disease manifestation as well. FIPV infects the target cell, macrophages, more efficiently, spread to other susceptible cells faster, and sustained the infection better than FECV. Despite several virulence related genes, i.e., spike, membrane, 3c, and 7b, have been proposed, the actual role of the mutation of these genes is unclear. In this study, full length of accessory gene 3c was cloned and the effect of the expression of 3C protein on the FCoV harboring a truncated accessory gene 3c is assessed. The 3C protein is confirmed to play an inhibitory role in the viral replication, which may be associated with the low virulence of FECV, and this effect is independent to the autophagy pathway.
Due to the lack of vaccine and therapy, the suggested clinical management of FIP is euthanasia that causes an enormous financial, emotional and ethical impact. To search the agents with potential therapeutic effect, the anti-FCoV activity of 16 commercially available compounds belongs to four categories, i.e., nucleoside analogue, protease inhibitor, reverse transcriptse inhibitor, and compounds with other activities, were examined. Among all the compounds tested, nelfinavir, a protease inhibitor, and Galanthus nivalis agglutinin, a mannose-binding lectin, were found to exhibit a significant anti-FCoV effect. In addition, the combination of these two compounds were demonstrated to complete inhibit the viral replication, synergistically.
Despite the antiviral compounds with therapeutic potential were identified, as FIP cats presented in the clinics are usually at the late stage of the disease, the effect of therapy is often very limited. In order to prevent the occurrence of disease more efficiently, the identification of the disease-associated genetic polymorphism in cats was attempted. Expression of several cytokines was shown to be significantly altered in FIP cats when compared to the FCoV-infected non-FIP cats. Among the cytokines that have been studied, the transcription level and plasma concentration of IFN-γ is consistently decreased in FIP cats. Since the polymorphisms of IFN-γ gene in human have been demonstrated to be associated with various virus infections and immune-mediated diseases. In order to identify the possible genetic factor associated with the occurrence of FIP, a survey of feline IFN-γ gene were conducted in 63 FIP cats and 82 asymptomatic cats from our teaching hospital during the past six years. Sixteen single nucleotide polymorphisms were successfully identified in the intron 1, and three of them, i.e., polymorphisms at position +401, +408, and +428, were found significantly associated with the occurrence of FIP. In addition, polymorphism at position+428 also showed a clear correlation with the plasma concentration of IFN-γ in FIP cats. Since the disease-associated polymorphism could be used as a marker for the selection of FIP-resistant cats, three genotyping methods using amplification refractory mutation system polymerase chain reaction and restriction fragment length polymorphism for fIFNG+401, +408, and +428 were established in this study. These selection markers could be utilized for the further identification of FIP-resistant and -susceptible cats, and decrease the occurrence of FIP in cats populations.
Subjects
貓冠狀病毒
貓傳染性腹膜炎
3C蛋白
細胞自噬作用
抗病毒藥物
宿主基因因子
γ-干擾素
SDGs
Type
thesis
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