Pathogenicity and virulence of Francisella tularensis

ABSTRACTTularaemia is a zoonotic disease caused by the Gram-negative bacterium, Francisella tularensis. Depending on its entry route into the organism, F. tularensis causes different diseases, ranging from life-threatening pneumonia to less severe ulceroglandular tularaemia. Various strains with different geographical distributions exhibit different levels of virulence. F. tularensis is an intracellular bacterium that replicates primarily in the cytosol of the phagocytes. The main virulence attribute of F. tularensis is the type 6 secretion system (T6SS) and its effectors that promote escape from the phagosome. In addition, F. tularensis has evolved a peculiar envelope that allows it to escape detection by the immune system. In this review, we cover tularaemia, different Francisella strains, and their pathogenicity. We particularly emphasize the intracellular life cycle, associated virulence factors, and metabolic adaptations. Finally, we present how F. tularensis largely escapes immune detection to be one of the most infectious and lethal bacterial pathogens

Comparative study of GBP recruitment on two cytosol-dwelling pathogens, Francisella novicida and Shigella flexneri highlights differences in GBP repertoire and in GBP1 motif requirements

International audienceAbstract Guanylate-Binding Proteins are interferon-inducible GTPases that play a key role in cell autonomous responses against intracellular pathogens. Despite sharing high sequence similarity, subtle differences among GBPs translate into functional divergences that are still largely not understood. A key GBP feature is the formation of supramolecular GBP complexes on the bacterial surface. Such complexes are observed when GBP1 binds lipopolysaccharide (LPS) from Shigella and Salmonella and further recruits GBP2-4. Here, we compared GBP recruitment on two cytosol-dwelling pathogens, Francisella novicida and S. flexneri. Francisella novicida was coated by GBP1 and GBP2 and to a lower extent by GBP4 in human macrophages. Contrary to S. flexneri, F. novicida was not targeted by GBP3, a feature independent of T6SS effectors. Multiple GBP1 features were required to promote targeting to F. novicida while GBP1 targeting to S. flexneri was much more permissive to GBP1 mutagenesis suggesting that GBP1 has multiple domains that cooperate to recognize F. novicida atypical LPS. Altogether our results indicate that the repertoire of GBPs recruited onto specific bacteria is dictated by GBP-specific features and by specific bacterial factors that remain to be identified

Bacterial factors drive the differential targeting of Guanylate Binding Proteins to <i>Francisella</i> and <i>Shigella</i>

ABSTRACTGuanylate-Binding Proteins (GBPs) are interferon-inducible GTPases that play a key role in cell autonomous responses against intracellular pathogens. Seven GBPs are present in humans. Despite sharing high sequence similarity, subtle differences among GBPs translate into functional divergences that are still largely not understood. A key step for the antimicrobial activity of GBPs towards cytosolic bacteria is the formation of supramolecular GBP complexes on the bacterial surface. Such complexes are formed when GBP1 binds lipopolysaccharide (LPS) from Shigella and Salmonella and further recruits GBP2, 3, and 4.Here, we investigated GBPs recruitment on Francisella novicida, a professional cytosol-dwelling pathogen with an atypical tetra-acylated LPS. Co-infection experiments demonstrated that GBPs target preferentially S. flexneri compared to F. novicida. F. novicida was coated by GBP1 and GBP2 in human macrophages but escaped targeting by GBP3 and GBP4. GBP1 and GBP2 features that drive recruitment to F. novicida were investigated revealing that GBP1 GDPase activity is required to initiate GBP recruitment to F. novicida but facultative to target S. flexneri. Furthermore, analysis of chimeric GBP2/5 proteins identified a central domain in GBP2 necessary and sufficient to target F. novicida. Finally, a F. novicida ΔlpxF mutant with a penta-acylated lipid A was targeted by GBP3 suggesting that lipid A tetra-acylation contributes to escape from GBP3. Altogether our results indicate that GBPs have different affinity for different bacteria and that the repertoire of GBPs recruited onto cytosolic bacteria is dictated by GBP-intrinsic features and specific bacterial factors, including the structure of the lipid A.IMPORTANCEFew bacteria have adapted to thrive in the hostile environment of the cell cytosol. As a professional cytosol-dwelling pathogen, S. flexneri secretes several effectors to block cytosolic immune effectors, including GBPs. This study illustrates a different approach of adapting to the host cytosol: the stealth strategy developed by F. novicida. F. novicida bears an atypical hypoacylated LPS, which does not elicit neither TLR4 nor caspase-11 activation. Here, this atypical LPS was shown to promote escape from GBP3 targeting. Furthermore, the lower affinity of GBPs for F. novicida allowed to decipher the different domains that govern GBP recruitment to the bacterial surface. This study illustrates the importance of investigating different bacterial models to broaden our understanding of the intricacies of host-pathogen interactions.</jats:sec