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 findings expand the role of a well-established family of antiviral restriction factors to control of a major bacterial pathogen. In a previous study, no difference was found in lung bacterial load between wild-type and Ifitm3 −/− C57BL/6 mice at 30 days post-aerosol infection with H37Rv-MTb . However, only early time points (<30 days) post-infection were evaluated in this study, and it is clear that many immunological factors important for TB control become evident only at later stages in mice (Mayer-Barber and Sher, 2015) . We previously demonstrated, for example, that MTb lung burden is equivalent at 6 weeks post-infection in wild-type mice and mice deficient in the transcription factor NFATp, but the NFATp −/− mice succumbed more rapidly (median 119 versus 205 days) and lung bacterial burden was 10 3 higher in these mice at the time of death/sacrifice (Via et al., 2012) . In another example, MTb lung burden was higher in IL-6-deficient versus wild-type mice early after infection, but the IL-6 −/− mice contained bacterial growth at later time points (Saunders et al., 2000) . Moreover, while three IFITMs have been identified in humans, mice possess four Ifitm genes (Sällman Almén et al., 2012; Zhang et al., 2012) , suggesting that redundancy among the IFITMs may have precluded clear identification of a phenotype. Finally, although the murine TB model has proved valuable for the elucidation of immunoregulatory pathways involved in TB control that also are critical in humans, inflammatory responses in mice, particularly at the level of monocyte/macrophage function and TLR activation, are imperfect representatives of what occurs in humans (Seok et al., 2013) , and the challenge strain used by Everitt et al. (2013) , H37Rv, is less virulent than clinical strains (Palanisamy et al., 2009; Park et al., 2006) . Thus, the study of TB in Ifitm3 −/− C57BL/6 mice does not rule out a role for IFITM3, or the IFITM family, in the innate immune response to TB.