Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes.
Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes.
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猫冠状病毒（fcov）通常在全世界的猫科动物中引起轻微的肠道感染（称为猫肠道冠状病毒[FECV]），其中约12%发展为致命的猫传染性腹膜炎（FIP；猫传染性腹膜炎病毒[FIPV]）。FECV和FIPV之间的基因组差异已被报道，但高致病性表型的假定基因型基础仍不清楚。在这里，我们使用最先进的分子进化遗传统计技术来识别和比较FECV和FIPV序列之间自然选择压力的差异，以及识别FIPV和FECV特异性的正选择信号。我们分析了被认为包含FIPV相关突变的全长FCoV蛋白编码基因（Spike、ORF3abc和ORF7ab）。我们确定了FECV和FIPV之间表现出自然选择压力差异的两个位点：一个在S1/S2 furin切割位点（FCS）内，另一个在Spike的融合域内。我们还在Spike中发现了15个与FIPV相关的阳性选择位点，其中11个位点以前没有被认为可能与FIP的发展有关。这些位点位于参与宿主细胞受体相互作用、免疫逃避、趋向性转移、宿主细胞进入和病毒逃逸的Spike蛋白亚域内。在Spike中有14个位点（12个新位点）处于与FECV表型相关的正选择下，几乎全部位于S1/S2 FCS内并毗邻C结构域，并且FIPV中相对于FECV有一个放松选择的信号，这表明FIPV可能不需要furin切割功能。ORF7b中推断的正选择与FECV表型相关，包括24个正选择位点，而ORF7b在FIPV中具有放松选择的信号。我们在fcov全范围分析中发现ORF3c阳性选择的证据，但与FIPV或FECV表型没有特异性关联。我们假设FECV中的一些突变组合可能有助于FIP的发展，并且它不太可能是一个单一的“开关”突变事件。这项工作扩大了我们对FIP发展复杂性的理解，并为进化力量如何改变冠状病毒基因组的发病机制提供了见解。
Feline coronaviruses (FCoVs) commonly cause mild enteric infections in felines worldwide (termed feline enteric coronavirus [FECV]), with around 12 per cent developing into deadly feline infectious peritonitis (FIP; feline infectious peritonitis virus [FIPV]). Genomic differences between FECV and FIPV have been reported, yet the putative genotypic basis of the highly pathogenic phenotype remains unclear. Here, we used state-of-the-art molecular evolutionary genetic statistical techniques to identify and compare differences in natural selection pressure between FECV and FIPV sequences, as well as to identify FIPV- and FECV-specific signals of positive selection. We analyzed full-length FCoV protein coding genes thought to contain mutations associated with FIPV (Spike, ORF3abc, and ORF7ab). We identified two sites exhibiting differences in natural selection pressure between FECV and FIPV: one within the S1/S2 furin cleavage site (FCS) and the other within the fusion domain of Spike. We also found fifteen sites subject to positive selection associated with FIPV within Spike, eleven of which have not previously been suggested as possibly relevant to FIP development. These sites fall within Spike protein subdomains that participate in host cell receptor interaction, immune evasion, tropism shifts, host cellular entry, and viral escape. There were fourteen sites (twelve novel sites) within Spike under positive selection associated with the FECV phenotype, almost exclusively within the S1/S2 FCS and adjacent to C domain, along with a signal of relaxed selection in FIPV relative to FECV, suggesting that furin cleavage functionality may not be needed for FIPV. Positive selection inferred in ORF7b was associated with the FECV phenotype and included twenty-four positively selected sites, while ORF7b had signals of relaxed selection in FIPV. We found evidence of positive selection in ORF3c in FCoV-wide analyses, but no specific association with the FIPV or FECV phenotype. We hypothesize that some combination of mutations in FECV may contribute to FIP development, and that it is unlikely to be one singular ‘switch’ mutational event. This work expands our understanding of the complexities of FIP development and provides insights into how evolutionary forces may alter pathogenesis in coronavirus genomes.
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影响因子：
2.4
作者：
Kiss I;Kecskeméti S;Tanyi J;Klingeborn B;Belák S
通讯作者：
Belák S
影响因子：
11.8
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Chang HW;Egberink HF;Halpin R;Spiro DJ;Rottier PJ
通讯作者：
Rottier PJ
影响因子：
11.8
作者：
Brown, Meredith A.;Troyer, Jennifer L.;O'Brien, Stephen J.
通讯作者：
O'Brien, Stephen J.
影响因子：
1.7
作者：
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
通讯作者：
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影响因子：
1.8
作者：
Brown, Meredith A.
通讯作者：
Brown, Meredith A.