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 1

Increased KSHV infection in senescent human endothelial cells.

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Increased KSHV infection in senescent human endothelial cells. (A) Senes...
(A) Senescence was induced in primary human endothelial cells (HUVECs) by repeated subculture over 35 passages or treatment with doxorubicin. In doxycycline-inducible immortalized human endothelial cells (HuARLT cells), senescence was induced by culturing without doxycycline. SA-β-gal staining was used for validation of senescence through microscopy or flow cytometry. p, cell culture passages. dc, doxycycline. KSHV infectivity was measured by GFP expression in cells infected with recombinant KSHV BAC16. (B) Analysis of KSHV-infected cells in nonsenescent and senescent human endothelial cells by flow cytometry at 24 hpi. Data are representative of 3 independent experiments. Data are shown as mean ± SD. n = 3. ***P < 0.001, unpaired 2-tailed Student’s t test. (C) Quantification of the KSHV genome in KSHV-infected nonsenescent and senescent human endothelial cells by quantitative PCR at 24 hpi. 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. (D) Assessment of the relative expression of KSHV ORF71 mRNA in KSHV-infected nonsenescent and senescent human endothelial cells using quantitative reverse transcription PCR at 24 hpi. Data are representative of 3 independent experiments. Data are shown as mean ± SD. n = 3. **P < 0.01, unpaired 2-tailed Student’s t test.