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Updated: Apr 22, 2026
Characterizing Salmonella Typhimurium-induced Septic Peritonitis in Mice
Published on: July 29, 2022
Salmonella-derived haem inhibits macrophage phagocytosis and promotes infection in mice
Zuoqiang Wang1, Huang Tang1, Wanqiu Huang1
1Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Bacterial pathogens such as Salmonella enterica serovar Typhimurium can resist phagocytosis by macrophages. Here we explored the role of bacterial haem biosynthesis in phagocytosis resistance. Using transposon sequencing (Tn-seq) during Salmonella infection of macrophages, we identify a methyltransferase, SirM, that indirectly inhibits phagocytosis of bacteria. Mechanistically, sirM is activated upon interaction with macrophages and methylates HemL, a key enzyme in haem biosynthesis, resulting in upregulation of haem synthesis by Salmonella. Salmonella-derived haem inhibits Cdc42 activation in a Toll-like receptor 4 (TLR4)-dependent manner to inhibit phagocytosis. Moreover, sirM promotes macrophage death by increasing haem synthesis. Experiments in mouse models show that sirM is required for virulence and confers a competitive advantage over intestinal commensal bacteria during infection. We also found that sirM is distributed among enteric pathogens. Collectively, our findings show that bacterial haem promotes evasion of phagocyte responses and pathogenesis to confer an advantage in the host.
Insights
Salmonella Typhimurium uses bacterial haem synthesis to resist macrophage phagocytosis. The SirM enzyme activates haem production, inhibiting immune responses and promoting bacterial virulence.
Area of Science:
- Microbiology
- Immunology
- Bacterial Pathogenesis
Background:
- Bacterial pathogens like Salmonella Typhimurium can evade host immune defenses, specifically resisting phagocytosis by macrophages.
- Understanding the mechanisms behind this immune evasion is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of bacterial haem biosynthesis in the ability of Salmonella Typhimurium to resist phagocytosis by macrophages.
- To identify bacterial factors involved in this process and elucidate their mechanisms of action.
Main Methods:
- Utilized transposon sequencing (Tn-seq) to screen for genes affecting Salmonella survival during macrophage infection.
- Employed biochemical assays to study the methylation of HemL by SirM and its effect on haem synthesis.
- Investigated the inhibition of Cdc42 activation and phagocytosis using cell-based assays.
- Validated findings in mouse models of infection.
Main Results:
- Identified SirM, a methyltransferase, as a key regulator of Salmonella's resistance to phagocytosis.
- Demonstrated that SirM is activated by macrophage interaction, leading to HemL methylation and increased bacterial haem synthesis.
- Showed that Salmonella-derived haem inhibits Cdc42 activation via Toll-like receptor 4 (TLR4), thereby preventing phagocytosis.
- SirM was found to promote macrophage death and enhance Salmonella virulence and competitive advantage in vivo.
- SirM was also found to be prevalent among other enteric pathogens.
Conclusions:
- Bacterial haem biosynthesis, regulated by SirM, is a critical mechanism for Salmonella to evade host phagocyte responses.
- This pathway contributes to pathogenesis by inhibiting immune cell function and promoting bacterial survival and virulence.
- The findings highlight bacterial haem as a potential target for antimicrobial strategies.
