SARS-CoV-2 infection triggers paracrine senescence – the inflammatory response persists even after the virus has disappeared


Researchers from Osaka University-Japan, have in a new study found that SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response that could also be responsible for a variety of conditions seen in Long COVID.

Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production.

In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable.

We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome.

The study findings were published in the peer reviewed journal: Nature Aging.

As COVID-19 tends to be more severe in older people, some important clues may exist in the relationship between SARS-CoV-2 infection and aging.
Though numerous changes in various biological responses are associated with aging, the accumulation of senescent cells has recently attracted keen attention. Cellular senescence is a state of irreversible cell-cycle arrest that can be induced by a variety of potentially oncogenic stimuli and thus is considered to serve as an important mechanism of tumor suppression.

However, unlike apoptotic cells, senescent cells do not die immediately and thereby accumulate throughout the body during the aging process.

Importantly, senescent cells are not merely nondividing, as they also develop a phenomenon called the SASP in which they secrete a variety of proinflammatory factors, such as inflammatory cytokines, chemokines, growth factors and extracellular matrix-degrading enzymes, into the extracellular fluid.
Thus, although the induction of cellular senescence acts primarily as a mechanism of tumor suppression, the excessive accumulation of senescent cells in vivo due to aging is thought to have adverse effects via SASP.
Indeed, the removal of senescent cells by genetic or pharmacological approaches reportedly delays the onset of aging-associated inflammatory diseases in aged mice.
These previous findings prompted the study team to examine the relationship between cellular senescence and SARS-CoV-2 infection.
The study team first set up a system to infect senescent cells with SARS-CoV-2 using primary normal human lung diploid fibroblasts (HDFs), which are commonly used in senescence studies.
 Interestingly, the expression level of the ACE2 gene, which is required for SARS-CoV-2 to enter the cells, was increased several-fold upon the induction of cellular senescence in HDFs, as well as in other cultured primary normal human cells.
 This is fairly consistent with the previous observation that the levels of the ACE2 gene expression are slightly increased in lung tissues with age.
 The study team however were unable to detect SARS-CoV-2 infection in these primary normal human cells, regardless of cellular senescence induction.
 However, the study team unexpectedly noticed that signs of cellular senescence, such as cell-cycle arrest, induction of expression of p16INK4a, one of the proteins encoded by the CDKN2a gene locus5 and interleukin-1β (IL-1β) (SASP factor) expression were observed on day 9 after SARS-CoV-2 administration.
This is somewhat consistent with previous reports that certain viral infections can directly induced senescence-like features in cultured cells.


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