Senescence of endothelial cells increases susceptibility to Kaposi’s sarcoma–associated herpesvirus infection via CD109-mediated viral entry
Myung-Ju Lee, … , Shou-Jiang Gao, Myung-Shin Lee
Myung-Ju Lee, … , Shou-Jiang 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-Jiang Gao, Myung-Shin Lee

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Figure 5

Establishment and characterization of KO clones for the candidate proteins in HuARLT cells.

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Establishment and characterization of KO clones for the candidate protei...
(A) Schematic diagram of the gRNA sequence for caveolin-1 (CAV1), integrin α2 (ITGA2), F11R, and CD109. The gRNA-recognizing site is indicated as the CRISPR target sequence. (B) Western blot analysis of each KO protein. WT, WT HuARLT cell; KO, KO HuARLT cell. (C) Target sequence analysis in WT and KO HuARLT cells. The PCR products containing the gRNA targeting region from the genomic DNA of WT and KO cells were cloned into a T-vector. The sequences of 10 colonies were analyzed by Sanger sequencing. The mutated region is indicated by a box.