Potential threats of porcine Getah virus outbreaks and its specific antagonism of host antiviral response through proteasome-dependent degradation of P46 by nsP2

Alphaviruses are a genus of positive-strand RNA viruses classified in the Togaviridae family. It contains many important human and animal pathogens, such as chikungunya virus (CHIKV), Sindbis virus (SINV), Venezuelan equine encephalitis virus (VEEV), Semliki Forest virus (SFV) and Ross River virus (RRV), posing significant threats to public health and animal welfare. As a member of genus Alphavirus, porcine Getah virus (GETV) is re-emerging around in many parts of the world in recent years (2022-2025) and has caused small to large-scale outbreaks of diarrhea related diseases in pig industry. In this study, a virulent porcine GETV (JLy1 strain) was isolated from the intestinal contents of diarrheic piglets. Using AG129 mouse as an infection model, all the infected mice succumbed to JLy1 infection accompanied by the severe intestinal damages. Further studies indicated that GETV also caused diarrhea and damages to the intestine, lung and spleen in 2-day-old piglets, leading to 100% mortality. Meanwhile, a host protein P46 was screened to be obviously downregulated in GETV infected intestinal tissues, suggesting a potential regulatory relationship between GETV infection and endogenous P46 expression. Ectopic expression of P46 inhibits GETV infection, whereas P46 knockout by CRISPR-Cas9 editing significantly promotes GETV replication, indicating P46 as a novel antiviral regulator against GETV infection. Further studies demonstrated that GETV employs a unique mechanism to antagonizes P46 antiviral response via Lys48-linked proteasome-dependent degradation compared to other alphaviruses, including CHIKV, VEEV, SINV, SFV and RRV. Our findings provide insights into the outbreak risks and immune evasion mechanisms of re-emerging GETV, advancing our understanding of GETV pathogenesis.