Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection

• Published in: Nature communications Vol. 11; no. 1; p. 3535
• Main Authors: Sivangala Thandi, Ramya, Radhakrishnan, Rajesh Kumar, Tripathi, Deepak, Paidipally, Padmaja, Azad, Abul K, Schlesinger, Larry S, Samten, Buka, Mulik, Sachin, Vankayalapati, Ramakrishna
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15-07-2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acetylcholine; Ammonia - chemistry; Animals; Apoptosis; Arginase - chemistry; Atropine; Atropine - pharmacology; Autophagy; Autophagy - drug effects; Bone marrow; Cell Proliferation; Cytochrome; Cytochrome P450; Cytochromes P450; Disease Progression; Female; Hepatocytes; Imidazole; Imidazoles - pharmacology; Infections; Kupffer cells; Kupffer Cells - drug effects; Kupffer Cells - microbiology; Macrophages; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - microbiology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - microbiology; Metabolites; Metabolomics; Mice; Mice, Inbred C57BL; Monocytes; Mycobacterium tuberculosis; Nitric Oxide - chemistry; Ornithine; Ornithine - pharmacology; Peritoneum; Phagocytes; Phagocytosis; Phosphatidylserines - chemistry; Reactive Oxygen Species - chemistry; RNA, Small Interfering - metabolism; Tuberculosis; Tuberculosis - drug therapy; Urea; Urea - chemistry
• ISSN: 2041-1723
• DOI: 10.1038/s41467-020-17310-5

Macrophages are professional phagocytes known to play a vital role in controlling Mycobacterium tuberculosis (Mtb) infection and disease progression. Here we compare Mtb growth in mouse alveolar (AMs), peritoneal (PMs), and liver (Kupffer cells; KCs) macrophages and in bone marrow-derived monocytes (BDMs). KCs restrict Mtb growth more efficiently than all other macrophages and monocytes despite equivalent infections through enhanced autophagy. A metabolomics comparison of Mtb-infected macrophages indicates that ornithine and imidazole are two top-scoring metabolites in Mtb-infected KCs and that acetylcholine is the top-scoring in Mtb-infected AMs. Ornithine, imidazole and atropine (acetylcholine inhibitor) inhibit Mtb growth in AMs. Ornithine enhances AMPK mediated autophagy whereas imidazole directly kills Mtb by reducing cytochrome P450 activity. Intranasal delivery of ornithine or imidazole or the two together restricts Mtb growth. Our study demonstrates that the metabolic differences between Mtb-infected AMs and KCs lead to differences in the restriction of Mtb growth.