Francisella Inflammasomes: Integrated Responses to a Cytosolic Stealth Bacterium

Abstract

Francisella tularensis is a facultative intracellular bacterium causing tularemia, a zoonotic disease. Francisella replicates in the macrophage cytosol and eventually triggers cytosolic immune responses. In murine macrophages, Francisella novicida and Francisella tularensis live vaccine strain lyse in the host cytosol and activate the cytosolic DNA receptor Aim2. Here, we review the mechanisms leading or contributing to Aim2 inflammasome activation, including the role of TLRs and of IFN signaling and the implication of the guanylate-binding proteins 2 and 5 in triggering cytosolic bacteriolysis. Furthermore, we present how this cytosolic Gram-negative bacterium escapes recognition by caspase-11 but can trigger a non-canonical caspase-8 inflammasome. In addition, we highlight the differences in inflammasome activation in murine and human cells with pyrin, NLRP3, and AIM2 involved in sensing Francisella in human phagocytes. From a bacterial prospective, we describe the hiding strategy of Francisella to escape recognition by innate sensors and to resist to bacteriolysis in the host cytosol. Finally, we discuss the inability of the inflammasome sensors to detect F. tularensis subspecies tularensis strains, making them highly pathogenic stealth microbes.

Inflammasome-mediated antagonism of type I interferon enhancesRickettsiapathogenesis

“…From these observations, we conclude that bacteriolysis is likely responsible for the release of LPS and DNA that stimulate caspase-11 and cGAS. In contrast with what we observed for R. parkeri , several facultative bacterial pathogens have evolved different mechanisms to avoid the inflammasome (Jorgensen and Miao, 2015), including modification LPS by F. novicida to avoid caspase-11 (Hagar et al, 2013; Wallet et al, 2016), downregulation of flagellin by L. monocytogenes to avoid NAIP5 (Miao et al, 2010; Shen and Higgins, 2006), and infrequent lysis by F. tularensis and L. monocytogenes to avoid AIM2 (Sauer et al, 2010; Ulland et al, 2010). We propose that inflammasome activation is a trade-off that allows for growth of a pathogen that is sensitive to IFN-I.…”

“…The innate immune response to microbial pathogens depends on upregulation of antimicrobial factors, secretion of cytokines, and activation of host cell death pathways (Jorgensen and Miao, 2015; Meunier and Broz, 2016; Mitchell and Isberg, 2017; Randow et al, 2013). Innate immune responses have been characterized during infection with facultative intracellular bacterial pathogens such as Listeria monocytogenes and virulent Francisella species, as well as viruses, which inhabit the host cell cytosol (Brubaker et al, 2015; McNab et al, 2015; Wallet et al, 2016). However, less well understood are the innate immune responses to obligate intracellular bacterial pathogens.…”

“…Pyroptosis curtails microbial replication and exposes microbes to the extracellular environment where they can be targeted by immune factors such as phagocytes and antibodies. To avoid inflammasome activation, F. novicida modifies its LPS, enabling it to avoid caspase-11 (Hagar et al, 2013; Wallet et al, 2016). Additionally, L. monocytogenes and F. novicida minimize bacteriolysis to prevent the release of DNA (Peng et al, 2011; Sauer et al, 2010), and L. monocytogenes downregulates expression of flagellin (an activator of the inflammasome) during infection (Shen and Higgins, 2006).…”

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

“…Considered together, the available data suggest that opsonization with natural IgG is one factor that contributes to the inability of F. novicida to cause human disease. Inasmuch as opsonization with IgG is sufficient for NADPH oxidase activation and ROS production, the ability of the absent in melanoma 2 inflammasome to curtail F. novicida growth in macrophages may be critical, and IL-1b released during macrophages pyroptosis is another factor that may contribute to prolonged neutrophil survival [32]. Thus, in the context of F. novicida infection, it is conceivable that delayed neutrophil apoptosis favors phagocytic killing of bacteria released by dying macrophages.…”

“…Studies of isolated phagocytes and animal models demonstrate that F. novicida exhibits only some of the same virulence attributes and mechanisms as F. tularensis. In particular, F. novicida is markedly more proinflammatory, as indicated by analyses of TLR signaling, proinflammatory cytokine production, and inflammasome activation, which significantly diminish bacterial replication in macrophages and favor host defense [30][31][32]. In addition, we have shown that these organisms are opsonized by different mechanisms upon incubation in 50% normal human serum, with natural IgG binding to F. novicida eliciting neutrophil NADPH oxidase activation that does not occur following natural IgM binding to F. tularensis [16,[33][34][35][36].…”