IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection

Abstract

Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners.

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

“…Tularemia vaccination also induced changes in 23 early signatures that were not seen after other vaccines, including greater induction of members of the GBP family that are known to be induced by IFN-γ [30] and have been linked with control of Francisella infection in mice [31]. Although several interferon-inducible genes were associated with YF-17D, LAIV, and TIV, upregulation of GBPs was unique to tularemia.…”

Sensing of invading pathogens by GBPs: At the crossroads between cell-autonomous and innate immunity

“…More specifically, mGBPs regulate programmed cell death pathways involving caspases 3, 8, and 9. 45 The same group also showed that, contrary to the mouse caspase-11, the human homologue caspase-4 is able to detect cytosolic tetra-acylated LPS that has been released from F. novicida. Interestingly, hGBP2 contributes to the activation of the caspase-4 noncanonical inflammasome in human macrophages upon F. novicida infection, 46 similarly to what has been observed for mGBP2 in promoting caspase-11 activation in response to L. pneumophila infection.…”

“…It was recently shown that mGBPs also contribute for AIM2‐independent cell death upon F. novicida infection. More specifically, mGBPs regulate programmed cell death pathways involving caspases 3, 8, and 9 . The same group also showed that, contrary to the mouse caspase‐11, the human homologue caspase‐4 is able to detect cytosolic tetra‐acylated LPS that has been released from F. novicida .…”

IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE

“…GBPs are a family of dynamin-related large GTPases that are expressed in response to IFNs and other proinflammatory cytokines to mediate a broad range of pathogen-induced innate immune responses (41). In immune cells, GBPs activate NLRP3 and AIM2 inflammasomes in conjunction with bacterial signals to induce pyroptosis (42)(43)(44)(45)(46)(47). Together, these data suggest that another potential mechanism of enhanced NETosis in risk neutrophils is via IFN signaling because IFNs are reported to prime neutrophils for NETosis (38,(48)(49)(50).…”