Kaposi's sarcoma (KS) is one of the most common cancers in HIV-positive patients, and frequently occurs in the oral mucosa, skin, and lymph nodes due to KS Herpes Virus (KSHV) infection. Proliferating KS tumor cells are believed to originate from blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs), as KS cells express the signature genes of both cell types. LECs and BECs are closely related because LECs are derived from BECs during development, thus their gene expression profiles remain similar even after development. Despite their similarities, these two types of endothelial cells exhibit significant differences in their KSHV pathologies. One of the most recognized differences is that LECs are much more permissive to KSHV infection than BECs. Although this differential infectivity was first described more than a decade ago, neither rigorous follow-up characterization, nor elucidation of the underlying molecular basis, of this important lineage-specific phenotype are understood to date. In the current study, we propose to study the molecular underpinnings of the increased KSHV infectivity in LECs. We hypothesize that CEACAM1 and CEACAM6 proteins function as a novel KSHV receptor predominantly expressed in LECs, enabling the increased permissiveness of LECs. Accordingly, we will identify and characterize these CEACAMs (Aim1) and dissect the interactions between KSHV and these CEACAM proteins (Aim2). The outcome of this study will not only define the molecular basis of the enhanced permissiveness of LECs to KSHV infection, but also provide new knowledge on lymphatic-specific KSHV pathologies. In sum, this project will advance our current understanding of KSHV-host cell interactions, help broaden therapeutic options against KS, and offer important insight into the histogenetic origin of KS.

Public Health Relevance

Kaposi's sarcoma (KS) is one of the most common cancers in HIV-positive patients, and caused by infection of endothelial cells in the oral mucosa and skin with KS Herpes Virus (KSHV). This study will identify the mechanism by which KSHV infect preferably lymphatic endothelial cells, over blood vascular endothelial cells. The outcome of this study will deliver a significant impact to our current understanding of KS pathogenesis with important therapeutic implication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE027891-02
Application #
9717229
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Chander, Preethi
Project Start
2018-06-07
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Southern California
Department
Surgery
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089