INTRODUCTION: Aging is correlated with increased mortality during influenza A virus pneumonia. A model to investigate the impact of aging is the use of TERC ko/ko mice, characterized by accelerated telomere shortening and telomerase independent impact on cell cycle and inflammation. Within lung tissue, alveolar type 2 (AT2) cells serve as progenitor cells, crucial for maintaining lung homeostasis. Aged AT2 cells display indications of cellular senescence and heightened inflammatory signaling. Therefore, these cells are of special interest for analyzing the pathomechanisms during influenza virus infection.

GOALS: Investigation of the impact of telomerase dysfunction and the telomerase independent role of TERC on the immune response and disease manifestation during respiratory virus infection.

MATERIALS & METHODS: TERC-ko/ko and WT mice were intranasal infected with influenza A virus for 2 and 21 days. Viral load was quantified via plaque assay, cytokine secretion was measured by using flow cytometry and surfactant A protein was determined via ELISA. To further determine the infection event, a murine ex vivo infection model of lung slices was used. mRNA-sequencing of infected AT2 cells from TERC ko/ko mice was performed.

RESULTS: We observed a severe disease progression in TERC ko/ko mice during the first 10 days of influenza A virus infection. Throughout the acute phase, TERC ko/ko mice showed lower viral load in the lungs with a significantly higher pro-inflammatory cytokine response and surfactant protein A production. These results were confirmed using a murine ex vivo lung model. To further analyze the infection process, global transcriptome response of infected primary AT2 cells from TERC ko/ko and WT mice was performed. We identified a dysregulation in the inflammatory host response and cell cycle, as evidenced by the PI3/Akt pathway.

SUMMARY: TERC ko/ko mice exhibited an increased susceptibility to influenza A virus infection. Specifically, evidence from AT2 cells suggests that the knockout of TERC contributes to restricted proliferation, elevated inflammatory response, and impaired surfactant function in the lung.