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

Authors

• Baojun Yang, University of Texas at Tyler
• Tanmoy Mukherjee, University of Texas at Tyler
• Rajesh Radhakrishnan, University of Texas at Tyler
• Padmaja Paidipally, University of Texas at Tyler
• Danish Ansari, University of Texas at Tyler
• Sahana John, University of Texas at Tyler
• Ramakrishna Vankayalapati, University of Texas at Tyler
• Deepak Tripathi, University of Texas at Tyler
• Guohua Yi, University of Texas at Tyler

Document Type

Article

Publication Date

4-12-2023

Abstract

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. © 2023 by the authors.

Description

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Persistant Identifier

http://hdl.handle.net/10950/5191

Publisher

Multidisciplinary Digital Publishing Institute (MDPI)

Recommended Citation

Yang, Baojun; Mukherjee, Tanmoy; Radhakrishnan, Rajesh; Paidipally, Padmaja; Ansari, Danish; John, Sahana; Vankayalapati, Ramakrishna; Tripathi, Deepak; and Yi, Guohua, "HIV-Differentiated Metabolite N-Acetyl-L-Alanine Dysregulates Human Natural Killer Cell Responses to Mycobacterium tuberculosis Infection" (2023). School of Medicine Faculty Publications and Presentations. Paper 43.