Distinct post-infectious TLR2 immune remodeling in COVID-19-recovered centenarians

Exceptional longevity has increasingly been recognized as a distinct biological state associated with unique immune and inflammatory profiles. However, the innate immune characteristics associated with extreme aging, particularly following viral infections, remain incompletely understood. Toll-like receptors (TLRs) play central roles in pathogen sensing and inflammatory signaling, including during SARS-CoV-2 infection, yet their relationship with exceptional longevity has not been clearly defined. Here, we quantified TLR gene expression in peripheral blood from unvaccinated older adults who recovered from COVID-19 prior to vaccination (38 nonagenarians and 8 centenarians). Among the receptors analyzed, TLR2 was the only gene differentially expressed, showing lower expression in COVID-19-recovered centenarians compared with recovered nonagenarians. Importantly, this difference was not associated with COVID-19 severity, suggesting that TLR2 expression in this cohort reflects an age- and recovery-associated immune characteristic rather than clinical outcome. Exploratory comparison with centenarians without prior COVID-19 (n = 10) indicated that reduced TLR2 expression was not simply a constitutive hallmark of extreme aging, but may instead reflect a distinct post-infectious innate immune remodeling. Together, these findings identify a distinct TLR2-associated immune signature in centenarians recovered from COVID-19 and suggest that exceptional longevity may be associated with a distinct post-infectious innate immune remodeling following SARS-CoV-2 infection.