RETRACTED ARTICLE: Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection

Ramya Sivangala Thandi, Rajesh Kumar Radhakrishnan, Deepak Tripathi, Padmaja Paidipally, Abul K. Azad, Larry S. Schlesinger, Buka Samten, Sachin Mulik and Ramakrishna Vankayalapati ()
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Ramya Sivangala Thandi: University of Texas Health Center
Rajesh Kumar Radhakrishnan: University of Texas Health Center
Deepak Tripathi: University of Texas Health Center
Padmaja Paidipally: University of Texas Health Center
Abul K. Azad: Texas Biomedical Research Institute
Larry S. Schlesinger: Texas Biomedical Research Institute
Buka Samten: University of Texas Health Center
Sachin Mulik: University of Texas Health Center
Ramakrishna Vankayalapati: University of Texas Health Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17310-5

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