TTV virome marks immune exhaustion, α7nAChR alteration, and mortality in elderly patients with severe COPD

Torque teno virus (TTV) viremia, part of the human virome, is emerging as a dynamic marker of immune competence, yet its links to immune exhaustion, cholinergic dysfunction, and poor outcomes in elderly patients with severe COPD remain unclear. In 102 elderly COPD patients (age 72.6 ± 8.8 years, GOLD stage 3-4) undergoing a 3-week pulmonary rehabilitation program, TTV load was measured, and peripheral blood mononuclear cells were analyzed for T-cell subsets and α7 nicotinic acetylcholine receptor (α7nAChR) expression. Patients with high TTV load (≥ 4 log₁₀/mL) exhibited profound T-cell depletion, increased regulatory T cells (Treg), and reduced α7nAChR expression (31% vs. 52%, p = 0.023), indicating impaired cholinergic immune control. Five-year survival was shorter (609 ± 160 vs. 937 ± 94 days, p = 0.017), with Treg percentage-but not TTV load-being the only independent predictor of mortality. High TTV was also associated with lower BMI, higher smoking prevalence, and more depressive symptoms. These results suggest that elevated TTV reflects immune exhaustion and altered cholinergic receptor expression rather than direct viral pathogenicity, highlighting its role as a multidimensional biomarker of immune competence, cholinergic dysfunction, and prognosis specifically in elderly patients with severe COPD, who are more susceptible to immunosenescence, frailty, and comorbidity-driven complications, with potential implications for personalized rehabilitation strategies.