Senescence and Host–Pathogen Interactions

Abstract

Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

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 ].…”

“…Senescence has also lately been identified as a potential antiviral defense mechanism to aid in activating the immune system to clear the infection. However, prolonged exposure to cellular damage that occurs during HIV infection leads to an increase in cellular senescence, which ultimately leads to an accumulation of chronic inflammation and immune failure [ 57 , 58 ]. Each of these factors ultimately contributes to increased incidence of age-related comorbidities, such as neurodegenerative, cardiovascular, and metabolic diseases, and cancers, in PLHIV [ 51 , 53 , 59 , 60 , 61 ].…”

The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

“…The typhoid toxin (TT), which was originally discovered and characterized in S. Typhi ( 14 , 15 ), has been proposed as a key player in the development of typhoid fever, acting at both the single-cell and systemic levels in models of infection ( 14 , 16 – 19 ). The TT incorporates the nuclease activity of the CdtB subunit of the cytolethal distending toxin (CDT) ( 14 , 20 ) with the mono-ADP-ribosyltransferase activity of the pertussis toxin (called PltA), resulting in a hybrid toxin that induces a DNA damage response (DDR) in eukaryotic cells, leading to an accumulation of cells in the G 2 /M cell cycle phase ( 17 , 18 ) and subsequent senescence ( 21 , 22 ). The resulting damaged DNA is proposed to play a role in both disease manifestation ( 18 ) and colonization and persistence of the toxin-producing bacteria in the host ( 19 , 23 ), although its role in acute typhoid fever remains uncertain ( 24 ).…”

Co‐ and polymicrobial infections in the gut mucosa: The host–microbiota–pathogen perspective

“…A novel aspect emerging from studies of the pathogen–host interaction field is the role of senescence (Humphreys, ElGhazaly, & Frisan, 2020). Senescence is a process by which cells, in response to diverse stress conditions, enter a permanent cell cycle arrest, but maintain a high metabolic state characterized by secretion of a plethora of soluble mediators, a feature known as senescence‐associated secretory phenotype (SASP) (Gorgoulis et al, 2019).…”

“…A novel aspect emerging from studies of the pathogen-host interaction field is the role of senescence (Humphreys, ElGhazaly, & Frisan, 2020). Ibler et al, 2019;Kim, Seong, & Shin, 2016;Lim et al, 2010;Shivshankar, Boyd, Le Saux, Yeh, & Orihuela, 2011).…”