TRIM29 knockout pigs exhibit enhanced broad-spectrum disease resilience by amplifying type I interferon antiviral defenses

TL;DR

Scientists created pigs that are more resistant to multiple viruses by removing a gene that weakens the immune response.

Contribution

Gene-edited pigs with enhanced broad-spectrum antiviral defenses through TRIM29 knockout.

Findings

TRIM29 knockout pigs showed improved survival and milder symptoms after PRV infection.

Alveolar macrophages from TRIM29-KO pigs were resilient to PRV, VSV, and TGEV.

TRIM29-KO pigs had elevated type I IFN levels, enhancing antiviral immunity.

Abstract

While production traits have seen accelerated genetic improvement through advanced breeding technologies, disease resilience phenotypes continue to pose significant challenges in livestock breeding system. Current gene editing technologies provide an effective and biosafe strategy to enhance livestock disease resilience through precise manipulation of host antiviral genes. In this study, we successfully generated disease-resilient pigs exhibiting broad-spectrum antiviral activity against multiple viruses, with no observed adverse effects on pig health. The E3 ubiquitin ligase TRIM29 functions as a negative regulator of type I interferon (IFN) signaling, thus representing a potential antiviral target. Knockdown of TRIM29 in PK15 cells significantly enhanced antiviral immunity against pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) by augmenting type I IFN production. Translationally, we generated Trim29 knockout (KO) mice and confirmed their enhanced antiviral ability to both PRV and VSV infections. Subsequently, we produced TRIM29-KO pigs via gene editing coupled with somatic cell nuclear transfer. Compared to wild-type controls, the TRIM29-KO pigs exhibited significantly enhanced resilience to PRV infection, which was associated with elevated type I IFN levels in vivo. Furthermore, alveolar macrophages derived from TRIM29-KO pigs showed reduced susceptibility to infection with PRV, VSV, and transmissible gastroenteritis virus (TGEV), highlighting their potential broad-spectrum antiviral activity against multiple viral pathogens.

Pigs were domesticated about 9000 years ago, but infectious diseases still represent the biggest constraint on modern pig production. Traditional breeding has improved growth and lean meat content, yet cannot keep up with rapidly evolving viral pathogens. The 20th and 21st centuries have seen severe pig pandemics that caused massive global economic losses. Conventional disease control, relying on biosecurity, vaccination, and eradication, is inherently reactive, often entailing high costs and suboptimal efficacy. The disease burden urgently calls for a shift from disease control to genetic resilience in pigs. Gene editing is a practical tool for agricultural genetic improvement. Several edited crops and livestock have gained commercial approval recently, making it feasible to breed disease-resilient pigs and break the epidemiological bottleneck. We here generated the gene-edited pigs with enhanced disease resilience, by knockout of the negative regulator of type I interferon (IFN), TRIM29. Upon PRV infection, these pigs showed improved survival and milder symptoms, correlating with stronger antiviral IFN response. Primary cells from the edited pigs were also resilient to VSV and TGEV infection. This work provides a novel pig resource with broad-spectrum disease resilience, offering potential benefits for improving pig health and combating pandemics in the pig industry.

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