Salmonella-derived haem inhibits macrophage phagocytosis and promotes infection in mice PMID: 42009756

ADC Targets in Oncology

2026-04-10

Salmonella-derived haem inhibits macrophage phagocytosis and promotes infection in mice

Nat Microbiol. 2026 Jun;11(6):1722-1738. doi: 10.1038/s41564-026-02341-3.

Zuoqiang Wang ^# ¹ , Huang Tang ^# ¹ , Wanqiu Huang ^# ¹ , Chengyue Wang ¹ , Yana Chen ² , Jingchen Yu ¹ , Tao Zhou ¹ , Bingjie Wen ¹ , Jinjing Ni ¹ , Danni Wang ¹ , Jing Tao ¹ , Siqi Zhu ³ , Lin Lyu ⁴ , Lei Chen ⁴ , Jun Li ⁵ , Qihong Kuang ⁶ , Daojin Yu ⁶ , Jianping Liu ⁷ , Lifeng Pan ⁷ , Mei Zhang ⁸ , Yue Xu ⁹ , Guo-Ping Zhao ¹⁰ , Jie Lu ¹¹ , Yu-Feng Yao ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Department of Pediatrics, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Hefei, China.
3. South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
4. Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5. College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang, China.
6. Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, China.
7. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
8. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
9. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
10. CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.
11. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
12. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
13. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
14. State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
15. Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China. [email protected].
# Contributed equally.

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.