A Role for IFITM Proteins in Restriction of Mycobacterium tuberculosis Infection

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

MTb triggers signaling by the pattern recognition receptors (PRRs) Toll-like receptor (TLR)2 and TLR4, leading to the activation of innate immune response genes (Means et al., 1999; Underhill et al., 1999; reviewed in Falvo et al., 2011) . As shown in Figure 1C , activation of THP-1 cells with the TLR2 agonist Pam3Cys or with the TLR4 agonist lipopolysaccharide (LPS) significantly induced IFITM1-3 gene expression, which reached levels comparable to what was seen with live MTb infection by 48 hr post-stimulation. Upon engagement of TLR2 or TLR4, the adaptor molecule MyD88 transmits signals to downstream kinases, including IRAK1 and TRAF6, which mediate activation of the MAPK and NF-κB pathways and innate immune gene synthesis (Deguine and Barton, 2014; Falvo et al., 2011) . As shown in Figure 1D , when MyD88 expression was depleted in THP-1 cells by small hairpin RNA (shRNA), MTb-induced IFITM1-3 mRNA synthesis was impaired significantly, indicating that this signaling adaptor participates in IFITM gene induction by MTb. We obtained similar results in THP-1 cells in which IRAK1 or TRAF6 expression was ablated ( Figure S1 ), indicating that TLR-mediated MyD88 signaling directly leads to IFITM transcription.