Manganese transport systems of two enteric bacteria enhance their resistance to stress and enable the bacteria to evade the innate immune responses

Abstract

Manganese (Mn) is an important element in bacteria-host interactions, exerting significant functions on both bacterial physiology and host immune responses. The importance of bacterial Mn transport systems in mediating bacterial stress resistance has been recognized, however, its role in modulating host innate immunity during infections remained elusive. This study aimed to explore the functions of the Mn transport proteins MntH and SitABCD in two enteric pathogens, Enterohemorrhagic Escherichia coli (EHEC) and Salmonella enterica serovar Typhimurium. We demonstrate that mutants deficient in these Mn uptake transporters (EHEC ΔmntH and S. typhimurium ΔmntHΔsitA) exhibit markedly reduced resistance to extreme environmental conditions like oxidative stress and impaired competitive advantages. Importantly, EHEC ΔmntH and S. typhimurium ΔmntHΔsitA elicited a significantly stronger innate immune response in macrophages compared to wild-type strains, indicating that MntH and SitABCD play a crucial role in inhibiting host immune activation. Specifically, we observed that Mn²⁺ enhanced the innate immune response to infection, and such an effect was abrogated in cGas^−/− and Sting^−/− macrophages. Importantly, MntH and SitABCD suppress innate immune response via the STING pathway. In conclusion, this study showed that the Mn transport systems in EHEC and S. typhimurium play important roles in modulating host immune responses, highlighting the importance of Mn availability in shaping the outcomes of enteropathogenic bacterial infections.

Importance

The manganese (Mn) transport systems MntH and SitABCD are crucial for bacterial survival. This study elucidates the role of Mn transport in enhancing bacterial resilience to oxidative stress and modulating the host's innate immune system, focusing on Enterohemorrhagic Escherichia coli (EHEC) and Salmonella enterica serovar Typhimurium. Our findings demonstrate that Mn uptake transporters not only confer stress resistance but also play a significant role in attenuating host immune activation through the STING signaling pathway. Mutants lacking MntH and SitABCD showed increased immune activation, suggesting these transporters help bacteria evade detection. The findings reveal that manganese not only enhances bacterial stress resistance but also modulates immune activation, thereby influencing infection outcomes.