Determining the mechanistic basis for Irgm1 mediated control of Mycobacterium tuberculosis infection.

Abstract Irgm1 is a 47kDa IFN-γ inducible GTPase that has been shown to be essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. It was originally shown that Irgm1 is recruited to Mtb containing phagosomes in infected macrophages where it was proposed to be involved in autophagy-mediated clearance of Mtb. However, we have previously discovered that autophagy is not required in macrophages to control Mtb replication. In addition, it has since been reported that Irgm1 does not colocalize with phagosomes containing Mycobacterium bovis BCG in IFN-γ treated cells, suggesting that Irgm1 must have non-autophagic roles in TB infection that require detailed investigation. Irgm1 −/−mice were shown to have higher levels of type I interferon signaling, as well as CD4 +T cell survival defect, which could explain the susceptibility to Mtb infection, but this has yet to be determined. We infected Irgm1−/−mice with Mtb and found that they succumbed early to infection with higher bacterial burden, higher numbers of neutrophils, higher numbers of CD19 +B cells, and lower numbers of CD4 +T-lymphocytes in the lungs compared to wild-type (WT) mice. In addition, we found significantly increased expression of interferon-stimulated genes (ISGs) during Mtb infection of Irgm1−/−mice compared to WT. We also observed that T cell proliferation and lymph node responses were severely defective following Mtb infection in Irgm1−/−mice. Bone marrow chimera and transfer of Mtb-specific activated T lymphocytes into Irgm1−/−mice reverses the susceptibility to Mtb infection, indicating that a defect in T cell responses contributes to the susceptibility of Irgm1−/−mice to Mtb infection. This work was supported by Stephen I. Morse fellowship to Sumanta Kumar Naik and the Project supported by NIH AI142784 and AI132697 and BWF PATH Award to Dr. Christina Stallings.