Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis

Type VI secretion system (T6SS) is a versatile protein export machinery widely distributed in Gram-negative bacteria. Known to translocate protein substrates to eukaryotic and prokaryotic target cells to cause cellular damage, the T6SS has been primarily recognized as a contact-dependent bacterial weapon for microbe-host and microbial interspecies competition. Here we report contact-independent functions of the T6SS for metal acquisition, bacteria competition, and resistance to oxidative stress. We demonstrate that the T6SS-4 in Burkholderia thailandensis is critical for survival under oxidative stress and is regulated by OxyR, a conserved oxidative stress regulator. The T6SS-4 is important for intracellular accumulation of manganese (Mn²⁺) under oxidative stress. Next, we identified a T6SS-4-dependent Mn²⁺-binding effector TseM, and its interacting partner MnoT, a Mn²⁺-specific TonB-dependent outer membrane transporter. Similar to the T6SS-4 genes, expression of mnoT is regulated by OxyR and is induced under oxidative stress and low Mn²⁺ conditions. Both TseM and MnoT are required for efficient uptake of Mn²⁺ across the outer membrane under Mn²⁺-limited and -oxidative stress conditions. The TseM-MnoT-mediated active Mn²⁺ transport system is also involved in contact-independent bacteria-bacteria competition and bacterial virulence. This finding provides a perspective for understanding the mechanisms of metal ion uptake and the roles of T6SS in bacteria-bacteria competition.