BACTERIAL INDUCED HOST CELL FUSION, A NOVEL DANGER SIGNAL

Abstract

Cell-cell fusion leading to multinucleated giant cell (MNGC) formation is a Type Six Secretion System 5 (T6SS5) dependent phenotypic signature of Burkholderia pseudomallei infection believed to be important for facilitating cell-to-cell spread. We elucidate that T6SS5 induced cell fusion is also involved in upregulating type I interferon gene expression. Cell fusion activation of this immune response depends on the cGAS-STING signaling pathway known to detect cytosolic DNA. Our data suggest that cell fusion introduces DNA damage and genomic instability in the host cells through deregulated cell cycle events, which may allow extranuclear DNA to be made accessible to cGAS for its activation and downstream signaling for type I interferon gene induction. Activation of cGAS/STING against cell fusion during Burkholderia infection enhances cytotoxicity. We propose that aberrant cell fusion is a danger signal triggering DNA damage and an innate immune response, possibly functioning as a call for help against the pathogen.