Cellular senescence: friend or foe to respiratory viral infections?

Abstract

Cellular senescence permanently arrests the replication of various cell types and contributes to age-associated diseases. In particular, cellular senescence may enhance chronic lung diseases including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. However, the role cellular senescence plays in the pathophysiology of acute inflammatory diseases, especially viral infections, is less well-understood. There is evidence that cellular senescence prevents viral replication by increasing antiviral cytokines, but other evidence shows that senescence may enhance viral replication by downregulating antiviral signalling. Furthermore, cellular senescence leads to the secretion of inflammatory mediators, which may either promote host defense or exacerbate immune pathology during viral infections. In this perspective, we summarise how senescence contributes to physiology and disease, the role of senescence in chronic lung diseases, and how senescence impacts acute respiratory viral infections. Finally, we develop a potential framework of how senescence may contribute, both positively and negatively, to the pathophysiology of viral respiratory infections, including SARS-CoV-2.

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

“…Furthermore, the expression of critical proteins involved in mitochondrial biogenesis and mtDNA maintenance, including PGC-1α, ERR-α, NRF-1, and TFAM are significantly downregulated in aging cells or tissues [ 144 , 154 , 155 , 156 , 157 ]. Interestingly, age-linked associations have been made across a wide range of chronic viral infections, including but not limited to HIV, HCV, HBV, and CMV, as evidenced by increased telomere erosion and telomeric DNA damage, mitochondrial dysfunction, and cellular senescence [ 43 , 57 , 158 , 159 , 160 ].…”

“…Currently, there is conflicting evidence regarding the role of senescence in viral infection, primarily due to some new data implicating senescence in host antiviral defense via inhibiting viral replication, attracting innate immune cells, and activating cytokine signaling. Alternately, several investigations have shown that senescence is involved in the pathophysiology of viral infections via enhancing viral replication and suppressing antiviral type I IFN activation [ 160 ]. For example, RSV can cause DNA damage-induced senescence in lung epithelial and mononuclear cells in mice, ultimately leading to airway tissue remodeling and permanent tissue damage [ 58 ].…”

“…For example, RSV can cause DNA damage-induced senescence in lung epithelial and mononuclear cells in mice, ultimately leading to airway tissue remodeling and permanent tissue damage [ 58 ]. Additionally, influenza and herpes viruses have been shown to have increased viral replication in senescent cells [ 160 , 161 , 162 ]. Thus, it is likely that the dual role of senescence in virology is virus- and tissue-specific.…”

SARS-CoV-2 infects lung epithelial cells and induces senescence and an inflammatory response in patients with severe COVID-19

“…Viral infection has been associated with DNA damage and cell fusion, well-known inducers of senescence (4,6), and elicits release of pro-inflammatory mediators that may promote senescence via paracrine mechanisms (5). Therefore, senescence may act as a cellular defense mechanism against viral infection and increased prevalence of senescence could occur in infected and surrounding cells.…”

“…Therefore, senescence may act as a cellular defense mechanism against viral infection and increased prevalence of senescence could occur in infected and surrounding cells. Given the significance of systemic inflammation in the outcome of COVID-19, we have studied whether SARS-CoV-2 may be associated with cellular senescence in infected lung cells and the SASP phenotype (5). Immunocytochemistry: Immunohistochemistry was performed using: the anti-SARS-CoV-2 mAb (G2), which was produced and validated in house; anti-ACE-2 (Abcam); anti-Thyroid-Transcription-Factor(TTF)-1 (Dako); anti-CD68 (Dako); anti-p16 INK4A (Santa Cruz); IL-1β (Abcam) and IL-6 (R&D systems), as described (8).…”