Notably, ΔC16 virus infection led to similar penetrance of acholic stool, oily fur, weight loss, and mortality as the SA11 virus expressing RRV NSP1 (Fig 2D–2F), suggesting that an uncharacterized domain of NSP1 other than the IRF3-binding motif is involved in the extra-intestinal pathogenesis. Here, SH2D3A is linked to viral infectious disease.