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bioRxiv · 10.1101/2023.02.28.530445

HIV-differentiated metabolite N-Acetyl-L-Alanine dysregulates human natural killer cell responses to Mycobacterium tuberculosis infection

Yang, B.·Mukherjee, T.·Radhakrishnan, R.·Paidipally, P.·Ansari, D.·John, S.·Vankayalapati, R.·Tripathi, D.·Yi, G.
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Abstract

BackgroundMycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and causes 1.8 million deaths each year. 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 to the HIV-LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals. MethodsPlasma samples collected from healthy and HIV-infected individuals were investigated by liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using an online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, quantitative reverse transcription PCR (qRT-PCR) were performed by standard procedure to determine the surface markers, cytokines and other signaling molecule expression. Seahorse extra cellular flux assays were used to measure the mitochondrial oxidative phosphorylation and glycolysis. ResultsSix metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared to healthy donors. One of the HIV-upregulated metabolites, N-Acetyl-L-Alanine (ALA), inhibits pro-inflammatory cytokine IFN-{square} production by NK cells of LTBI+ individuals. ALA inhibits glycolysis of LTBI+ individuals NK cells in response to Mtb. ConclusionsOur 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 the implication of nutrition intervention and therapy for HIV-Mtb co-infected patients.

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Yang, B., Mukherjee, T., Radhakrishnan, R., Paidipally, P., Ansari, D., John, S., Vankayalapati, R., Tripathi, D., Yi, G.. 2023-03-01. HIV-differentiated metabolite N-Acetyl-L-Alanine dysregulates human natural killer cell responses to Mycobacterium tuberculosis infection. https://doi.org/10.1101/2023.02.28.530445

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