Senescence of endothelial cells increases susceptibility to Kaposi’s sarcoma–associated herpesvirus infection via CD109-mediated viral entry
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
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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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 6

Analysis of KSHV infectivity in KO clones of CAV1, ITGA2, F11R, and CD109.

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Analysis of KSHV infectivity in KO clones of CAV1, ITGA2, F11R, and CD10...
An equivalent quantity of KSHV was used to infect the same number of WT and KO HuARLT cells, with or without induction of senescence. KSHV was prepared as GFP infectious units of 1 to infect approximately 90% of nonsenescent WT cells, followed by the infection of a 2-fold serially diluted virus into each group of conditioned cells. KSHV infectivity was measured using GFP expression. (A and B) Fluorescence microscopic visualization of KSHV-infected cells for each KO clone in nonsenescent (+dc, A) and senescent (–dc, B) HuARLT cells. CAV1, caveolin-1; ITGA2, integrin-α2. Scale bar: 100 μm. (C and D) Flow cytometric analysis of KSHV-infected cells for each KO clone in nonsenescent (+dc, C) and senescent (–dc, D) HuARLT cells. At the indicated GFP infectious units (GIU), the percentage of KSHV-infected cells was compared among each group. Data are representative of 3 independent experiments. Data are shown as mean ± SD. n = 3. ***P < 0.001, Dunnett’s test for multiple comparisons.