Species-specific alternative splicing of SP110 drives tuberculosis susceptibility in cattle

Bovine tuberculosis (bTB) is a chronic debilitating zoonotic disease caused by Mycobacterium bovis (M. bovis). M. bovis exhibits a broad host range, but dairy cattle are particularly susceptible. The SP110 (speckled protein 110) gene has been demonstrated to be associated with host susceptibility to TB, but whether the susceptibility of dairy cattle to M. bovis is correlated with the bovine SP110 (bSP110) gene has not been investigated. Here, we demonstrated that the heightened susceptibility of dairy cattle to bTB was driven by species-specific alternative splicing of the bovine SP110 (bSP110) gene, which resulted in predominant expression of a truncated bSP110c variant lacking the SAND domain required for anti-bTB function. Compared to the other two splice variants of bSP110 gene, bSP110a and bSP110b, bSP110c showing significantly reduced resistance to M. bovis. Mechanistically, the ruminant-specific absence of a upstream of the SAND exon (designated as the pre-SAND exon) affects alternative splicing of the bSP110 gene, consequently promoting bSP110c production, while substituting this region with human/equine sequences introduces suppress bSP110c and increase bSP110a/b expression. Our study provides a new perspective on the genetic basis of the susceptibility of dairy cows to bTB and identifies a potential gene editing region for the breeding of tuberculosis-resistant dairy cows.