Telomerase RNA component knockout exacerbatesS. aureuspneumonia by extensive inflammation and dysfunction of T cells

Abstract

The telomerase RNA component (Terc) constitutes a non-coding RNA critical for telomerase function, commonly associated with aging and pivotal in immunomodulation during inflammation.Our study unveils heightened susceptibility to pneumonia caused byStaphylococcus aureus (S. aureus)inTercknockout (Tercko/ko) mice compared to both young and old infected counterparts. The exacerbated infection in Tercko/komice correlates with heightened inflammation, manifested by elevated interleukin-1β (IL-1β) levels and activation of the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome within the lung.Employing mRNA sequencing methods alongsidein vitroanalysis of alveolar macrophages (AMs) and T cells, our study elucidates a compelling correlation between Tercko/ko, inflammation, and impaired T cell functionality. Terc deletion results in compromised T cell function, characterized by dysregulation of the T cell receptor and absence of CD247, potentially compromising the host’s capacity to mount an effective immune response againstS. aureus.This investigation provides insights into the intricate mechanisms governing increased vulnerability to severe pneumonia in the context of Terc deficiency, which might also contribute to aging-related pathologies, while also revealing for the first time the influence of Terc on T cell function.Graphical abstract