Feline infectious peritonitis: insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene

Abstract

Feline infectious peritonitis (FIP) is a lethal systemic disease caused by FIP virus (FIPV), a virulent mutant of apathogenic 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 FECVs, 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 intestinal 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 Nidovirales), 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-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 (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 accompanied by accumulation of abdominal exudate (ascites; reviewed by de Groot & Horzinek,1995;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 cats. 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 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 isogenic to the original FECV strain yet, unlike the parental virus, induced FIP readily when inoculated into specific-pathogen-free cats (Poland et al., 1996;Vennema et al., 1998); virulence thus appears to be an acquired gene...

Sequence Analysis of Feline Coronaviruses and the Circulating Virulent/Avirulent Theory

“…Thus, as we observed earlier for the 3c gene ( 10 ), M gene sequences generally clustered according to the cattery from where they originated, irrespective of their pathotype (e.g., FECV 586 and FIPVs 584 and 585 from cattery A; FECV 620 and FIPVs 615 and 622 from cattery G; FECV 10 and FIPV 8 from cattery F). Such a distribution pattern is consistent with the mutation theory, according to which FIPVs originate from FECVs and are thus closely related ( 7 , 9 ).…”

Diversidade gênica do coronavírus felino em populações virais entéricas e sistêmicas intra e inter-hospedeiros

“…As this is the first report on FCoV diversity in Brazilian cats, further comparisons with other geographic areas within the country are an issue for future research. Recombination and a high mutation rate are common phenomena among coronaviruses, which provide a mechanism for the rapid emergence of new viral strains with dramatically altered tropisms and pathogenicity, which can have a significant impact on the host disease (HERREWEGH et al, 1997;VENNEMA et al, 1998;BROWN et al, 2009;PEDERSEN et al, 2009;CHANG et al, 2010). As both hypotheses have been found as plausible according to these results, this could mean that FIPV can both emerge endogenously and be transmitted to different cats as a "ready" virulent pathotype, which has major implications for the understanding of the dynamics of viral transmission.…”

“…Diversos estudos atribuem a diferença de virulência entre os patotipos aos genes S REGAN et al, 2008;CHANG et al, 2012;LICITRA et al, 2013), 3a-c (VENNEMA et al, 1998CHANG et al, 2010;BALINT et al, 2012;PEDERSEN et al, 2012;HSIEH et al, 2013) e 7ab (HERREWEGH et al, 1995a;KENNEDY et al, 2001;DEDEURWAERDER et al, 2014 ADDIE; JARRETT, 1992b;HERREWEGH et al, 1995b;. Certos gatos podem permanecer soropositivos por 10 anos ou mais , o que pode ser reflexo de infecções persistentes ou reinfecções .…”

“…No presente estudo, clones de genes estruturais (E e M) e acessórios (3a-c) Dados sugerem que os produtos dos genes 3a-c são pré-requisitos para a replicação do patotipo avirulento no trato entérico, mas alterações gênicas nesta região podem aumentar o fitness do vírus em replicação nos macrófagos e monócitos (CHANG et al, 2010;BALINT et al, 2012). A maioria das mutações observada ocorre no gene 3c do FIPV, mas também podem ser notadas nos genes 3a e 3b (VENNEMA et al, 1998;CHANG et al, 2010;PEDERSEN et al, 2012).…”

“…The hypothesis known as the "internal mutation theory" is widely accepted (POLAND et al, 1996;HERREWEGH et al, 1997;VENNEMA et al, 1998;PEDERSEN et al, 2009;CHANG et al, 2010;ROTTIER, 2011), and it states that FIP occurs when a cat is exposed to variants of FCoV that have mutated within the host and are able to disseminate from the gut (the primary site of infection) by gaining the ability to efficiently replicate within the macrophages (POLAND et al, 1996;VENNEMA et al, 1998). However, any stable genetic differences between FECoV and FIPV that can account for their differing pathogenicities remain to be identified (DYE; SIDDELL, 2007).…”