Senescence of endothelial cells increases susceptibility to Kaposi’s sarcoma–associated herpesvirus infection via CD109-mediated viral entry
Myung-Ju Lee, … , Shou-Jinag Gao, Myung-Shin Lee
Myung-Ju Lee, … , Shou-Jinag Gao, Myung-Shin Lee
Published December 12, 2024
Citation Information: J Clin Invest. 2025;135(4):e183561. https://doi.org/10.1172/JCI183561.
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Research Article Aging Virology

Senescence of endothelial cells increases susceptibility to Kaposi’s sarcoma–associated herpesvirus infection via CD109-mediated viral entry

Abstract

The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. However, the relationship between Kaposi’s sarcoma–associated herpesvirus (KSHV) infection, a cause of increased Kaposi’s sarcoma prevalence among the elderly without HIV infection, and cellular senescence remains enigmatic. This study uncovered a link between cellular senescence and enhanced KSHV infectivity in human endothelial cells. Through a comprehensive proteomic analysis, we identified caveolin-1 and CD109 as host factors significantly upregulated in senescent cells that promote KSHV infection. Remarkably, CRISPR/Cas9-mediated KO of these factors reduced KSHV binding and entry, leading to decreased viral infectivity. Furthermore, surface plasmon resonance analysis and confocal microscopy revealed a direct interaction between KSHV virions and CD109 on the cell surface during entry, with recombinant CD109 protein exhibiting inhibitory activity of KSHV infection by blocking virion binding. These findings uncover a previously unrecognized role of cellular senescence in enhancing KSHV infection through upregulation of specific host factors and provide insights into the complex interplay between aging and viral pathogenesis.

Authors

Myung-Ju Lee, Jun-Hee Yeon, Jisu Lee, Yun Hee Kang, Beom Seok Park, Joohee Park, Sung-Ho Yun, Dagmar Wirth, Seung-Min Yoo, Changhoon Park, Shou-Jinag Gao, Myung-Shin Lee

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Figure 2

Enhanced entry of KSHV in senescent human endothelial cells.

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Enhanced entry of KSHV in senescent human endothelial cells. (A) Immunof...
(A) Immunofluorescence assay of the entry of KSHV into nonsenescent and senescent cells. KSHV was visualized at 4 hpi using KSHV ORF65 antibody. Phalloidin (F-actin) and DAPI were used to visualize the shapes of the cells and nuclei, respectively. Scale bars: 50 μm. (B) Analysis of the number of internalized KSHV particles per cell in the images in A and Supplemental Figure 5. Data are representative of 10 independent experiments. Data are shown as mean ± SD. n = 10. ***P < 0.001 using unpaired 2-tailed Student’s t test. (C) Quantification of the internalized KSHV genome in the KSHV-infected nonsenescent and senescent human endothelial cells by quantitative PCR. Genomic DNA was extracted from KSHV-infected cells at 4 hpi. The KSHV genome was quantified in the extracted DNA by quantitative PCR using primers for KSHV ORF26. Data are representative of 3 independent experiments. Data are shown as mean ± SD. n = 3. **P < 0.01; ***P < 0.001, unpaired 2-tailed Student’s t test.