Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV

Abstract

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1β, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.

Development and Evaluation of a Nomogram for Predicting the Outcome of Immune Reconstitution Among HIV/AIDS Patients Receiving Antiretroviral Therapy in China

“…Appropriate unstimulated, unstain, isotype and single stain controls were included in all flow cytometry analyses, based on which the gates were determined in the analysis as previously described. [ 33 ] Tregs (CD4 + CD25 high CD127 −/Low ), resting Tregs (CD45RA + CD4 + CD25 high CD127 −/Low ), and effector Tregs (CD45RO + CD4 + CD25 high CD127 −/Low ) were acquired on a NovoCyte 2060R and analyzed using NovoExpress 14.1 (Agilent Technologies Inc.,).…”

Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review

“…In immune cells, IL-1 is found to regulate polyamine metabolism in various ways. It can upregulate enzymes involved in polyamine biosynthesis, boosting polyamine levels crucial for rapid immune cell proliferation during immune responses [ 35 , 36 ]. Furthermore, IL-1’s impact on polyamine metabolism supports tissue repair and wound healing by promoting immune cell proliferation and migration to damaged areas [ 37 ].…”

Critical Factors in Sample Collection and Preparation for Clinical Metabolomics of Underexplored Biological Specimens

“…The preparation of saliva samples for metabolomics analysis is quite simple. In general, the procedures involve protein precipitation with acetonitrile [ 189 , 190 , 191 , 192 , 193 , 194 , 195 ], methanol [ 196 , 197 , 198 ], or a combination of methanol/acetonitrile (1:1, v / v ) [ 199 , 200 , 201 ], methanol/water [ 202 , 203 , 204 , 205 , 206 ], and methanol/acetonitrile/water (2:2:1, v / v / v ) [ 207 ]. Other studies have used isopropanol [ 208 ] or acetone [ 209 ], which requires evaporation and resuspension in an appropriate solvent before chromatographic analysis.…”