Feline infectious peritonitis: Role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats

Abstract

Feline infectious peritonitis virus (FIPV) was presumed to arise from mutations in the 3c of a ubiquitous and largely nonpathogenic feline enteric coronavirus (FECV). However, a recent study found that one-third of FIPV isolates have an intact 3c and suggested that it is not solely involved in FIP but is essential for intestinal replication. In order to confirm these assumptions, 27 fecal and 32 FIP coronavirus isolates were obtained from resident or adopted cats from a large metropolitan shelter during 2008-2009 and their 3a-c, E, and M genes sequenced. Forty percent of coronavirus isolates from FIP tissues had an intact 3c gene, while 60% had mutations that truncated the gene product. The 3c genes of fecal isolates from healthy cats were always intact. Coronavirus from FIP diseased tissues consistently induced FIP when given either oronasally or intraperitoneally (i.p.), regardless of the functional status of their 3c genes, thus confirming them to be FIPVs. In contrast, fecal isolates from healthy cats were infectious following oronasal infection and shed at high levels in feces without causing disease, as expected for FECVs. Only one in three cats shed FECV in the feces following i.p. infection, indicating that FECVs can replicate systemically, but with difficulty. FIPVs having a mutated 3c were not shed in the feces following either oronasal or i.p. inoculation, while FIPVs with intact 3c genes were shed in the feces following oronasal but not i.p. inoculation. Therefore, an intact 3c appears to be essential for intestinal replication. Although FIPVs with an intact 3c were shed in the feces following oronasal inoculation, fecal virus from these cats was not infectious for other cats. Attempts to identify potential FIP mutations in the 3a, 3b, E, and M were negative. However, the 3c gene of FIPVs, even though appearing intact, contained many more non-synonymous amino acid changes in the 3' one-third of the 3c protein than FECVs. An attempt to trace FIPV isolates back to enteric strains existing in the shelter was only partially successful due to the large region over which shelter cats and kittens originated, housing conditions prior to acquisition, and rapid movement through the shelter. No evidence could be found to support a recent theory that FIPVs and FECVs are genetically distinct.

Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease

“…The underlying mechanisms that allow the tissue tropism change is reported to be associated with mutations in the S and open reading frame 3c genes and the aberrant immune response of the host, but the detailed mechanism of the altered tropism has not been clearly established (Chang et al, 2012a; Chang et al, 2011; Pedersen et al, 2012; Poland et al, 1996; Vennema et al, 1998). The feline enteric coronaviruses are present ubiquitously in the environment and easily transmitted via a fecal-oral route.…”

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

“…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 .…”

“…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).…”

“…É fundamental notar que o fato de apenas uma minoria das sequências observadas no cérebro do gato Hope possuir o gene 3c truncado poderia não ter sido detectado se o presente estudo avaliasse apenas a população viral predominante por meio de sequenciamento direto do amplicon, sem a aplicação da técnica de clonagem, como ocorreu nos estudos realizados até o momento por outros autores (PEDERSEN et al, 2009;CHANG et al, 2010;PEDERSEN et al, 2012;HSIEH et al, 2013). Em infecção experimental, a pressão para que a proteína 3c seja truncada é evidente (PEDERSEN et al, 2009).…”

“…Em infecção experimental, a pressão para que a proteína 3c seja truncada é evidente (PEDERSEN et al, 2009). Pedersen et al (2012) sugeriram que as mutações que causam a PIF não se iniciam com a terminação precoce da proteína 3c, portanto possivelmente o gato Hope (PIF+) poderia estar numa fase precoce da infecção, por apresentar apenas um clone do gene 3c truncado.…”