Molecular mechanism of the interaction between Megalocytivirus -induced virus-mock basement membrane (VMBM) and lymphatic endothelial cells.

The Megalocytivirus genus, family Iridoviridae, is a group of large DNA viruses that pose significant threats to marine and freshwater fishes. In tissues, the Megalocytivirus -infected cells are attached by a layer of lymphatic endothelial cells (LECs), constituting a unique histopathological phenomenon. Megalocytivirus induces the formation of an extracellular structure on the surface of infected cells that is functionally similar to the host basement membrane (BM), known as the virus-mock basement membrane (VMBM). VMBM is composed of host BM component nidogen-1 and viral proteins VP23R and VP08R and specifically provides adhesive support for LECs. In the current study, the viral protein VP33L was identified as a novel component of VMBM, and the way it participates in VMBM assembly was investigated. The interactions between virus-encoded VMBM components and LEC-specific markers lymphatic vessel endothelial receptor-1 (LYVE-1) and vascular endothelial growth factor receptor 3 (VEGFR-3), which contribute to the selective adhesion of LECs on VMBM, were further analyzed. Moreover, the viral components of VMBM could regulate the proliferation and migration of LECs via the VEGFR-3 signaling, which partially explains the origin of LECs attached to infected cells. This study is important for revealing the pathogenesis of Megalocytivirus and potentially provides reference clues for exploring the interaction mechanism between endothelial cells and extracellular matrix in animals. IMPORTANCE Viruses are able to mimic the physiological or pathological mechanism of the host to favor their infection and replication. Virus-mock basement membrane (VMBM) is a Megalocytivirus -induced extracellular structure formed on the surface of infected cells and structurally and functionally mimics the basement membrane of the host. VMBM provides specific support for lymphatic endothelial cells (LECs) rather than blood endothelial cells to adhere to the surface of infected cells, which constitutes a unique phenomenon of Megalocytivirus infection. Here, the structure of VMBM and the interactions between VMBM components and LECs have been analyzed at the molecular level. The regulatory effect of VMBM components on the proliferation and migration of LECs has also been explored. This study helps to understand the mechanism of LEC-specific attachment to VMBM and to address the issue of where the LECs come from in the context of Megalocytivirus infection.