Suppressive effects of pterostilbene on human cytomegalovirus (HCMV) infection and HCMV-induced cellular senescence

Abstract

Background Human cytomegalovirus (HCMV), a member of the β-herpesvirus family, causes the establishment of a latent infection that persists throughout the life of the host and can be reactivated when immunity is weakened. To date, there is no vaccine to prevent HCMV infection, and clinically approved drugs target the stage of viral replication and have obvious adverse reactions. Thus, development of novel therapeutics is urgently needed. Methods In the current study, we identified a naturally occurring pterostilbene that inhibits HCMV Towne strain replication in human diploid fibroblast WI-38 cells through Western blotting, qPCR, indirect immunofluorescence assay, tissue culture infective dose assays. The time-of-addition experiment was carried out to identify the stage at which pterostilbene acted. Finally, the changes of cellular senescence biomarkers and reactive oxygen species production brought by pterostilbene supplementation were used to partly elucidate the mechanism of anti-HCMV activity. Results Our findings revealed that pterostilbene prevented lytic cytopathic changes, inhibited the expression of viral proteins, suppressed the replication of HCMV DNA, and significantly reduced the viral titre in WI-38 cells. Furthermore, our data showed that pterostilbene predominantly acted after virus cell entry and membrane fusion. The half-maximal inhibitory concentration was determined to be 1.315 μM and the selectivity index of pterostilbene was calculated as 26.73. Moreover, cell senescence induced by HCMV infection was suppressed by pterostilbene supplementation, as shown by a decline in senescence-associated β-galactosidase activity, decreased production of reactive oxygen species and reduced expression of p16, p21 and p53, which are considered biomarkers of cellular senescence. Conclusion Together, our findings identify pterostilbene as a novel anti-HCMV agent that may prove useful in the treatment of HCMV replication.

Contribution of viral and bacterial infections to senescence and immunosenescence

“…Moreover, aging and viral infections seemingly influence HCMV-induced immune alterations that impair CD8 + T cell immunity later in life in a dose-dependent manner, which is related to HCMV-associated immune senescence ( Redeker et al., 2017 ). Noteworthy, it has been reported in human diploid fibroblast WI-38 cells that treatment with pterostilbene, a stilbenoid chemically related to resveratrol, reduces viral infection and has an inhibitory effect over molecular determinants related to cellular senescence and reactive oxygen species produced by this virus ( Wang et al., 2022 ).…”

DNA damage response(DDR): a link between cellular senescence and human cytomegalovirus

“…Furthermore, there is accumulating evidence that viral infection can generate oxidative stress [ 131 – 133 ], which can lead to DNA damage [ 74 , 75 ]. HCMV infection has been found to increase ROS generation [ 18 ] and mitochondrial biogenesis [ 134 ]. ROS promotes HCMV replication via paracrine and autocrine pathways, and N-acetylcysteine, a ubiquitous H 2 O 2 scavenger, decreases HCMV replication activation [ 135 ].…”