缺乏 CD163 蛋白 SRCR5 结构域的猪表现出对 PRRS 病毒的遗传抗性,且从出生到成熟的动物表现没有变化

IF 4.9 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Frontiers in genome editing Pub Date : 2024-03-13 DOI:10.3389/fgeed.2024.1322012
Clint Nesbitt, Lucina Galina Pantoja, Benjamin P Beaton, Ching-Yi Chen, Matt Culbertson, Perry Harms, Justin Holl, Andrzej Sosnicki, Srinu Reddy, Marisa L Rotolo, Elena Rice
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引用次数: 0

摘要

猪繁殖与呼吸综合征(PRRS)是世界上最顽固的猪病毒性疾病之一,对养猪业造成了重大的经济影响。PRRS 影响所有年龄段的猪,导致母猪晚期流产和死胎、仔猪呼吸道疾病、继发细菌感染和高死亡率。PRRS 疾病是由阳性单链 RNA PRRS 病毒(PRRSV)引起的,该病毒对宿主细胞的滋养范围很窄,仅限于单核-巨噬细胞系细胞。多项研究表明,去除 CD163 蛋白或至少去除其清道夫受体富半胱氨酸结构域 5 (SRCR5) 可阻止病毒基因组释放,从而使活体动物对 PRRSV 产生抗性。目前,关于此类编辑对猪从出生到成熟期的动物性能影响的信息非常有限。利用 CRISPR-Cas9 与双引导 RNA 和非同源末端连接 (NHEJ),生产出了 CD163 基因第 7 外显子缺失的第一代(E0)猪。选中的猪通过繁殖生产了下三代猪,建立了多个编辑等位基因同源的猪系,从而证实了去除了第 7 号外显子的 CD163 基因在多个繁殖周期中是稳定的。对这些猪从出生到成熟的整个过程进行了评估,包括肉质成分和对 PRRSV 抗性的潜在变化。这项研究表明,从 CD163 蛋白中移除 SRCR5 结构域可获得对 PRRSV 的抗性,而且与未编辑的猪相比,肉质成分没有发现差异,生长速度、健康状况和产仔能力也没有变化。总之,这些结果支持有针对性地在家畜中使用基因编辑技术来解决重大疾病问题,而不会对动物的健康和福祉或其衍生食品造成不利影响。
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Pigs lacking the SRCR5 domain of CD163 protein demonstrate heritable resistance to the PRRS virus and no changes in animal performance from birth to maturity
Porcine reproductive and respiratory syndrome (PRRS) is one of the world’s most persistent viral pig diseases, with a significant economic impact on the pig industry. PRRS affects pigs of all ages, causing late-term abortions and stillbirths in sows, respiratory disease in piglets, and increased susceptibility to secondary bacterial infection with a high mortality rate. PRRS disease is caused by a positive single-stranded RNA PRRS virus (PRRSV), which has a narrow host-cell tropism limited to monocyte–macrophage lineage cells. Several studies demonstrated that the removal of CD163 protein or, as a minimum, its scavenger receptor cysteine-rich domain 5 (SRCR5) precludes the viral genome release, conferring resistance to PRRSV in live animals. Today, very limited information exists about the impact of such edits on animal performance from birth to maturity in pigs. Using CRISPR–Cas9 with dual-guide RNAs and non-homologous end joining (NHEJ), first-generation (E0) pigs were produced with a deletion of exon 7 in the CD163 gene. The selected pigs were bred to produce the next three generations of pigs to establish multiple lines of pigs homozygous for the edited allele, thereby confirming that the CD163 gene with removed exon 7 was stable during multiple breeding cycles. The pigs were evaluated relative to non-edited pigs from birth to maturity, including any potential changes in meat composition and resistance to PRRSV. This study demonstrates that removing the SRCR5 domain from the CD163 protein confers resistance to PRRSV and, relative to unedited pigs, resulted in no detected differences in meat composition and no changes in the growth rate, health, and ability to farrow. Together, these results support the targeted use of gene editing in livestock animals to address significant diseases without adversely impacting the health and well-being of the animals or the food products derived from them.
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