Friday, May 9, 2025
5/9/2025
Amphiregulin-Immunometabolism axis in oral immunity and inflammation during HIV infection - ABSTRACT Systemic inflammation and mortality in people living with HIV (PLWH) are associated with mucosal immune dysfunction and persistent viral reservoirs in the mucosa and lymphoid tissues. In the previous project period, we have demonstrated the role of CD4+ FOXP3+regulatory T cells (Treg) dysregulation in contributing to aging- and HIV-associated oral inflammation. The dysfunctional Tregs that we uncovered in the oral mucosa of PLWH mimic tissue-resident CD4+ T cells expressing high levels of PD-1 and amphiregulin (AREG). These cells correlate with CD38+HLADR+ CD4+T cell hyperactivation and dysfunction, toll-like receptor 2 (TLR-2), and inflammasome/IL-1β signaling in vivo, and require IL-1β/AKT pathways for their expansion in the context of HIV infection. Here we propose to address the role of oral fungal dysbiosis in establishing the inflammatory environment and triggering oral immune cells to become dysfunctional. Building on our more recent results from salivary metabolome analysis in PLWH, we will examine the underlying pathways at the interface of dectin-1, AREG, inflammasome, and immunometabolism signaling pathways in three well-connected aims. Thus, our proposal will reveal new directions to manage oral immune-dysfunction and thereby systemic inflammation, and alter current clinical practice.
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