Francisella tularensis Live Vaccine Strain Folate Metabolism and Pseudouridine Synthase Gene Mutants Modulate Macrophage Caspase-1 Activation

Abstract

These findings further illustrate that F. tularensis LVS possesses numerous genes that influence its ability to activate the inflammasome, which is a key host strategy to control infection with this pathogen in vivo.

Repression of Inflammasome by Francisella tularensis during Early Stages of Infection

“…However, as reported in previous studies, we did not observe this NLRP3 dependence at 24 h post-infection either in F. tularensis LVS or the FTL_0325 mutant-infected macrophages. Similar to several previous reports, our results also demonstrate an AIM2-dependent but NLRP3-independent inflammasome activation at 16 -24 h post-infection in F. tularensis LVS-infected macrophages (34,35,48).…”

Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment

“…As previously reported, mice deficient in ASC (a critical component of several inflammasomes including the AIM2 inflammasome) were highly susceptible to infection with F. tularensis LVS with all ASC-deficient mice succumbing to infection by day 13 post infection (Fig. 5a; (refs 17, 18). However, NLRP3- or NLRP6-deficiency did not compromise the ability of mice to survive an i.n.…”

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

“…A hypercytotoxic phenotype also results from loss of oppB encoding a putative oligopeptide permease (13) or pepO, which may encode a metallopeptidase (13,14). Similar observations were made for live vaccine strain (LVS) deficient in folate metabolism or pseudouridine synthase genes (15), mviN, a putative lipid flippase (16), ripA, a cytoplasmic protein of unknown function (17), and kdhAB, encoding a Kdo hydrolase (18), or for Schu S4 variants lacking genes involved in lipopolysaccharide (LPS) O-antigen and capsule biosynthesis (19). One interpretation of these results is that Francisella has the ability to actively limit host cell death and that modulation of these cell death pathways involves a broad number of Francisella gene products.…”

“…However, the mechanisms by which F. tularensis avoids and suppresses other aspects of the host innate immune response are poorly defined (6)(7)(8)(9)(10)(11). Surveys for F. tularensis mutants that show heightened cytotoxicity or TLR2-dependent inflammatory responses has led to the identification of multiple unrelated gene products that contribute to this response (15)(16)(17)(18)(19). Although it is possible that some of the gene products identified are directly involved in subverting host innate immune response, the prevailing model is that these mutations alter the structural integrity of the cell resulting in either increased bacteriolysis during intracytosolic residence (20) or altered cell properties culminating in increased access of PRRs to otherwise inaccessible TLR ligands (18).…”