Our findings reveal the alternative function of Viperin on IFN-γ production in regulation of Mtb infection in macrophages, reinforce the idea of blocking IFN-γ production by Viperin deficiency as a host-directed therapy against TB, and raise the possibility that blocking a specific downstream step in IFN-γ signaling could protect macrophages from Mtb infection. Here, RSAD2 is linked to tuberculosis.