A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection

Ranjbar, Shahin; Haridas, Viraga; Jasenosky, Luke D.; Falvo, James V.; Goldfeld, Anne E.

Our data demonstrate that MTb infection induces IFITM gene expression. Previously, it was reported that LPS induces IFITM1 mRNA synthesis in human dendritic cells (Ishii et al., 2005) ; Ifitm1 and murine-specific Ifitm6 transcription in RAW264.7 macrophages (Han et al., 2011) ; and Ifitm3 gene expression in murine astrocytes, a process that was dependent on autocrine IFNb signaling (Nakajima et al., 2014) . We found that MyD88 KD reduces MTbinduced IFITM1-3 mRNA levels, demonstrating a direct role for TLRs and MyD88dependent autocrine/paracrine factors, such as IL-1β, in activation of these genes. Indeed, we found that IL-1β also induces IFITM1-3 transcription in human monocytes, extending previous findings that IL-1β activates IFITM3 mRNA synthesis in hepatocarcinoma cells and murine astrocytes (Nakajima et al., 2014) . As TNF and IL-6 also induced the transcription of IFITM1-3 in monocytes, it is likely that soluble factors produced during MTb infection further amplify PRR-driven IFITM1-3 mRNA levels. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which recently has been shown to trigger type I IFN synthesis in MTb-infected cells (Collins et al., 2015; Dey et al., 2015; Wassermann et al., 2015; Watson et al., 2015) , also may play a role in MTb-induced IFITM synthesis.