Senescent Cells May Enhance Viral Replication, Making Infections More Dangerous

An accumulation of senescent cells is one of the causes of degenerative aging. These cells secrete a mix of inflammatory and other signal molecules, producing numerous detrimental changes in surrounding tissues. As the number of senescent cells grows with advancing age, their presence causes dysfunction and pathology that contributes significantly to the progression of age-related disease. Researchers here provide evidence to suggest that, in addition to the range of harmful outcomes that are already fairly well known, the presence of senescent cells may also make viral infections worse, though the degree to which this is the case is a question mark:

Aging is suggested to be promoted by cellular senescence because senescent cells accumulate in tissues and organs with age. Replicative senescence refers to a stage which normal cells undergo growth arrest after proliferating for a limited number of population doublings. Influenza virus (IFV) and Varicella Zoster Virus (VZV) are the pathogens that cause the most common infectious diseases worldwide and the elderly populations are most vulnerable to IFV and VZV infections. The efficacy and effectiveness of influenza vaccines decrease with age, due to the negative impact of aging on the development of the immune system and its ability to function. The detailed role and mechanisms of senescence that underlie the increase in the levels of susceptibility to influenza infection have not been well elucidated.

Previous work has highlighted the age or senescence-associated decline of innate immune receptor function. For example, decreased toll-like receptor (TLR) function in dendritic cells, dysregulated signaling cascades, and decreased cytokine production have been shown to contribute to impaired innate immune responses. Similarly, age-associated defects in retinoic acid inducible gene-I (RIG-I) signaling specifically impairs interferon (IFN) signaling. In addition to gene expression changes in receptors, senescence is known to cause inflammaging, characterized by the up-regulation of the inflammatory response that occurs with advancing age. Altered secretion levels of pro-inflammatory cytokines and chemokines, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), were observed in elderly mice. These aberrant cytokine responses are thought to contribute to the inability of the elderly to mount appropriate immune responses to pathogens, vaccines, and self-antigens.

Human sirtuins are composed of a family of seven nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases that removes acetyl groups from wide ranges of essential proteins. SIRT1 has a broad range of physiological and biological functions, which play an important role in controlling gene expression, metabolism and aging. At cellular level, overexpression of SIRT1 was shown to prevent replicative senescence. Recent studies identified SIRT1 as an ancient antiviral defense factor. They showed that siRNA-mediated inhibition of each of the seven sirtuins could enhance the virus plaque formation for human cytomegalovirus (HCMV) and influenza A virus. The detailed mechanisms of SIRT1-mediated antiviral activities remain to be fully determined. In the present study, we used a replication-induced senescence in vitro model to illustrate the role and the mechanisms of senescence on viral replication and host response during viral infection.

In our study, we used two different virus infection models to examine the impact of replication-induced senescence and anti-senescence gene, SIRT1, on viral replication efficiency and host innate immune signaling pathways. A significant increase in viral replication efficiency was detected by replicative senescence during IFV and VZV infection. Furthermore, we confirmed that SIRT1 is an important antiviral factor, and SIRT inhibitor treatment or knockdown of SIRT1 resulted in the enhancement of virus plaque formation. As one of possible mechanisms for the increase in viral replication in senescent cells, a reduction in interferon (IFN) response after viral infection may account for it. Although DNA damage response caused by senescence-induced cell growth arrest can lead to increased basal expression levels of IFN and IFN-associated genes, our data suggests that virus-mediated induction of IFN and IFN-associated genes are down-regulated in senescent cells. Another possibility for the enhanced viral replication associated with senescence may largely attributed to the disruption of mitochondrial dynamics in that a defect in mitochondrial dynamics in senescent cells may contribute to down-regulation of early interferon response by inactivating the fission factor dynamin-related protein 1 (DRP1) in favor of viral replication. Further studies are required to test this hypothesis.

Among senescence-associated genes, SIRT1 is the best studied and currently considered to be the most important controlling factor involved in senescence and aging. Nicotinamide (NAM) is a well-known SIRT1 inhibitor and we wanted to assess whether NAM-mediated inhibition of deacetylase activity of SIRT1 was able to modulate viral replication. As expected, SIRT1 inhibition led to increased viral plaque formation. Recent studies also indicate that human SIRT1 shows a broad range antiviral function against DNA and RNA viruses, suggesting that sirtuin-modulating drugs can be used to treat viral diseases. Thus, sirtuin-modulating drugs can have a significant impact on the potential therapeutic approach for influenza infection. Considering that SIRT1 can be induced by viral infection and potentially affect the host immune response, further studies on the in vivo role of SIRT1 in determining susceptibility to viral infection may shed light on the function of SIRT1 in the amelioration of viral infection-associated symptoms.

In conclusion, our data demonstrate that cellular replicative senescence can contribute to increased viral replication. Furthermore, we provide the evidence that replicative senescence-associated changes could affect IFN expression, but not IFN-mediated antiviral response, which could result in an increased susceptibility of senescent cells to viral infection. A better understanding of immunosenescence during viral infection will greatly improve our knowledge of the pathogenesis of IFV and VZV and provide insight for therapeutic improvements in the response to IFV and VZV infection treatment in the elderly.