HIV-Differentiated Metabolite N-Acetyl-L-Alanine Dysregulates Human Natural Killer Cell Responses to IMycobacterium tuberculosis/I Infection

• Published in: International journal of molecular sciences Vol. 24; no. 8
• Main Authors: Yang, Baojun, Mukherjee, Tanmoy, Radhakrishnan, Rajesh, Paidipally, Padmaja, Ansari, Danish, John, Sahana, Vankayalapati, Ramakrishna, Tripathi, Deepak, Yi, Guohua
• Format: Journal Article
• Language: English
• Published: MDPI AG 01.04.2023
• Subjects: Amino acids; Comparative analysis; Development and progression; Enzyme-linked immunosorbent assay; Health aspects; HIV (Viruses); HIV infection; HIV patients; Immune response; Killer cells; Liquid chromatography; Mass spectrometry; Medical research; Medicine, Experimental; Metabolites; Scientific equipment and supplies industry; Tuberculosis; United States
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms24087267

Mycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and caused ~1.6 million deaths in 2021. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10-20 times compared with HIV- LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals. Plasma samples collected from healthy and HIV-infected individuals were investigated using liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using the online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, and quantitative reverse-transcription PCR (qRT-PCR) were performed using standard procedures to determine the surface markers, cytokines, and other signaling molecule expressions. Seahorse extra-cellular flux assays were used to measure mitochondrial oxidative phosphorylation and glycolysis. Six metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared with healthy donors. One of the HIV-upregulated metabolites, N-acetyl-L-alanine (ALA), inhibits pro-inflammatory cytokine IFN-γ production by the NK cells of LTBI+ individuals. ALA inhibits the glycolysis of LTBI+ individuals' NK cells in response to Mtb. Our findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK-cell-mediated immune responses to Mtb infection, offering a new understanding of the HIV-Mtb interaction and providing insights into the implication of nutrition intervention and therapy for HIV-Mtb co-infected patients.