Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.

Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4⁺ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4⁺ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications. [Display omitted] • T2D hosts exhibit impaired anti-viral Th1 responses • Hyperglycemia impedes Th1 differentiation by triggering lipid peroxidation (LPO) • LPO induces protein carbonylation of STAT4 and accelerates its degradation • LPO scavenger mitigates Th1 defects and improves viral control in T2D hosts Patients with T2D are more susceptible to severe viral respiratory infections, yet the underlying mechanism remains elusive. Here, Gray et al. reveal that hyperglycemia triggers lipid peroxidation (LPO) in CD4⁺ T cells. LPO-derived reactive carbonyl species modify STAT4 and expedite its degradation, leading to diminished anti-viral Th1 responses. [ABSTRACT FROM AUTHOR]