IL-6 promotes human cytomegalovirus infection of endothelial cells 2973

Description Inflammation is a double-edged sword that initiates tissue repair, but if sustained, causes damage that may benefit viral propagation. Certain viruses that have evolved to persist within the host drive cycles of chronic injury and inflammation that are difficult to resolve. Human cytomegalovirus (HCMV)–the prototypical β-herpesvirus and an opportunistic pathogen–persistently infects endothelial cells and contributes to their dysfunction. Low-level viral replication induces the secretion of type I interferons (IFN) and inflammatory cytokines (e.g., IL-6, IL-9, IL-5) that act in a paracrine manner to alarm neighboring cells via JAK/STAT signaling pathways. Even though JAK/STAT-regulated pathways often restrict viral infection, my data demonstrate that HCMV exploits JAK1/JAK2-dependent signaling to efficiently spread in primary human endothelial cells. Since IFN-β and IL-6 similarly signal via JAK1 and JAK2, I pre-treated endothelial cells with each cytokine prior to infection. Unlike IFN-β, which seems to have no effect, IL-6 strongly enhances viral entry. Recent evidence shows that IL-6 enhances T-cell-driven endothelial injury that dampens antibody responses and enhances infection in preclinical models of bone marrow transplantation. Here, we identify an additional pro-viral role of IL-6 in HCMV entry into endothelial cells. Together, these data highlight IL-6 as an important therapeutic target that could limit viral propagation and tissue injury. Funding Sources Supported by LSUHS CCDS Malcolm-Feist Pre-doctoral Fellowship; T32HL155022; NIH AI116851; LSUHS Chancellor’s Aim High Award Topic Categories Viral Immunology (VIR)