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

( ) 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...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-04, Vol.24 (8), p.7267
Main Authors: Yang, Baojun, Mukherjee, Tanmoy, Radhakrishnan, Rajesh, Paidipally, Padmaja, Ansari, Danish, John, Sahana, Vankayalapati, Ramakrishna, Tripathi, Deepak, Yi, Guohua
Format: Article
Language:English
Subjects:
HIV Infections
Humans
Killer Cells, Natural
Mycobacterium tuberculosis
Tuberculosis
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Summary:( ) 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 Our findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK-cell-mediated immune responses to infection, offering a new understanding of the HIV- interaction and providing insights into the implication of nutrition intervention and therapy for HIV- co-infected patients.
ISSN:1422-0067
1422-0067
DOI:10.3390/ijms24087267