Kaposi's Sarcoma-Associated Herpesvirus Subversion of the Anti-Inflammatory Response in Human Skin Cells Reveals Correlates of Latency and Disease Pathogenesis.
KSHV is the etiologic agent for Kaposi's sarcoma (KS), a neoplasm that manifests most aggressively as multifocal lesions on parts of human skin with a propensity for inflammatory reactivity. However, mechanisms that control evolution of KS from a benign hyperplasia to the histologically complex cutaneous lesion remain unknown. In this study, we found that KSHV induces proteomic and morphological changes in melanocytes and melanoma-derived cell lines, accompanied by deregulation of the endogenous anti-inflammatory responses anchored by the MC1-R/ α -MSH signaling axis. We also identified two skin-derived cell lines that displayed differences in ability to support long-term KSHV infection and mapped this dichotomy to differences in (a) NF- κ B activation status, (b) processing and expression of KSHV latency-associated nuclear antigen isoforms putatively associated with the viral lytic cycle, and (c) susceptibility to virus-induced changes in expression of key anti-inflammatory response genes that antagonize NF- κ B, including MC1-R, POMC, TRP-1, and xCT. Viral subversion of molecules that control the balance between latency and lytic replication represents a novel correlate of KSHV pathogenesis and tropism in skin and underscores the potential benefit of harnessing the endogenous anti-inflammatory processes as a therapeutic option for attenuating cutaneous KS and other proinflammatory outcomes of KSHV infection in high-risk individuals.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Judith M
JM
Fontana
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Justin G
JG
Mygatt
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Katelyn L
KL
Conant
Department of Medicine and Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
Chris H
CH
Parsons
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Johnan A R
JA
Kaleeba