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1、Short Communication Feline infectious peritonitis: insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene Hui-Wen Chang, Raoul J. de Groot, Herman F. Egberink and Peter J. M. Rottier Correspondence Peter J. M. Rottier p.rottieruu.nl Virology
2、Division, Department of Infectious Diseases and Immunology, Veterinary Faculty, Utrecht University, Utrecht, The Netherlands Received 9 September 2009 Accepted 29 October 2009 Feline infectious peritonitis (FIP) is a lethal systemic disease caused by FIP virus (FIPV), a virulent mutant of apathogeni
3、c feline enteric coronavirus (FECV). We analysed the 3c gene a proposed virulence marker in 27 FECV- and 28 FIPV-infected cats. Our findings suggest that functional 3c protein expression is crucial for FECV replication in the gut, but dispensable for systemic FIPV replication. Whilst intact in all F
4、ECVs, the 3c gene was mutated in the majority (71.4%) of FIPVs, but not in all, implying that mutation in 3c is not the (single) cause of FIP. Most cats with FIP had no detectable intestinal feline coronaviruses (FCoVs) and had seemingly cleared the primary FECV infection. In those with detectable i
5、ntestinal FCoV, the virus always had an intact 3c and seemed to have been acquired by FECV superinfection. Apparently, 3c-inactivated viruses replicate not at all or only poorly in the gut, explaining the rare incidence of FIP outbreaks. Feline coronaviruses (FCoVs; family Coronaviridae, order Nidov
6、irales), important pathogens of cats, occur as two distinctly different pathotypes. Feline enteric coronavirus (FECV), the pathotype most common in the field, seems to be confined mainly to the intestinal tract and causes mild, often unapparent enteritis. The virus spreads efficiently via the faecal
7、oral route and, as infections may persist subclinically for up to a year and perhaps even longer (Herrewegh et al., 1997; Pedersen et al., 2008), FECV prevalence is high, reaching up to 90% seropositivity in multi-cat environments. The other pathotype, designated feline infectious peritonitis virus
8、(FIPV), occurs only sporadically. In sharp contrast to FECVs, FIPVs do not seem to be well-transmitted and they are highly virulent. By efficiently infecting macrophages and monocytes, FIPVs can escape from the gut and cause a lethal systemic disease with multi-organ involvement, in classical cases
9、accom- panied by accumulation of abdominal exudate (ascites; reviewed by de Groot Haijema et al., 2007; Pedersen, 2009). There is genetic and animal experimental evidence to indicate that the virulent pathotype evolves time and time again from the avirulent one by mutation in individual infected cat
10、s. Comparative sequence analysis of FCoV laboratory strains and field variants revealed that FECVs and FIPVs come in genetically closely related pairs, more identical to each other than to other FCoVs (Herrewegh et al., 1995b; Pedersen et al., 1981; Poland et al., 1996; Vennema et al., 1998). Direct
11、 support for the internal mutation hypothesis comes from an experiment in which cats with an immunosuppressive feline immunodeficiency virus infection were superinfected with FECV. A number of these animals developed FIP in response. The (systemic) virus variants isolated from the diseased cats were
12、 isogenic to the original FECV strain yet, unlike the parental virus, induced FIP readily when inoculated into specific-patho- gen-free cats (Poland et al., 1996; Vennema et al., 1998); virulence thus appears to be an acquired genetic trait. So far, the critical mutations that convert apathogenic FE
13、CV into FIPV have not been identified in the huge 29 kb FCoV RNA genome. Several genes, including the spike gene and the so-called group-specific genes 3c, 7a and 7b, have been suggested to be associated with the pathotypic switch (Kennedy et al., 2001; Rottier et al., 2005; Vennema et al., 1998). I
14、n particular, it has been noted that FIPV strains frequently carry mutations that inactivate the gene for 3c (Pedersen, 2009; Vennema et al., 1998), an accessory triple-spanningmembraneproteinwithapredicted topology similar to that of SARS coronavirus 3a (Oostra et al., 2006). Loss of 3c function th
15、us seemingly correlates with acquisition of virulence (Haijema et al., 2004; Pedersen, 2009; Vennema et al., 1998). Recently, the internal mutation theory as the basis for the pathotype switch was fundamentally challenged by Dye antisense, 59-CAGGAGCCAGAAGAAGACACTAA-39), applying 30 cycles of 94uC f
16、or 60 s, 50uC for 30 s and 72uC for 1 min, and an additional extension at 72uC for 7 min at the end of amplification. Thus, gene 3c sequences were obtained from the faeces of 27 apparently healthy FECV- infected cats as well as from organs, ascites or typical pyogranulomatous lesions of 28 cats with pathologically confirmed FIP (see Supplementary Table S1, available in JGV Online) collected during 20072008 in the Netherlands. In addition, from 17 of the 28 cats with confirmed FIP, faecal mat
