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

Robertson, Gregory T.; Case, Elizabeth Di Russo; Dobbs, Nicole; Ingle, Christine; Balaban, Murat Ö.; Celli, Jean; Norgard, Michael V.

doi:10.1128/iai.00102-14

Cited by 14 publications

(16 citation statements)

References 50 publications

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“…Conversely, the activation of the AIM2/ASC inflammasome plays a pivotal role in the innate immune response to F. tularensis, and leads to the control of bacterial replication both in macrophages and in vivo ( 34 -36 , 278). However, the F. tularensis protein encoded by FTL-0325 delays inflammasome activation during infection (279), possibly by contributing to the structural integrity of the bacterial surface rather than by actively repressing host inflammasome activation (280). Interestingly, it was recently shown that the S. flexneri T3SS effector OspC3 inhibits the induction of a non-canonical inflammasome by directly targeting caspase-4, the human ortholog of mouse caspase-11 (281).…”

Section: Manipulation Of Host Sensing Pathways By Cytosolic Bacteriamentioning

confidence: 99%

Strategies Used by Bacteria to Grow in Macrophages

Mitchell

Chen

Portnoy

2017

Myeloid Cells in Health and Disease

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Most intracellular bacteria replicate in myeloid cells, especially in macrophages (2 , 23). Macrophages are plastic cells characterized by their phenotypic diversity, and are involved in # important in the cytosolic response to nucleic acids (40 , 41) such as DNA (42) and cyclic dinucleotides (CDNs) (43), and triggers a type I IFN response upon bacterial infection. STING directly binds to cyclic dinucleotides (CDNs), but not to DNA, and is then both a direct sensor and an adaptor molecule (44). The host cytosolic DNA-sensor cGAMP synthase (cGAS) is able to synthesis cyclic GMP-AMP (cGAMP), which is an endogenous secondary messenger that binds and activates STING (45 , 46). Accordingly, cGAS is involved in the secretion of IFN-β following the detection of bacterial DNA in the host cytosol (47 -49). It is noteworthy that other cytosolic PRRs also contribute to nucleic acids sensing and induce a type I IFN response including DDX41 (50 , 51) and IFI16 (52).Besides antiviral immune response, the role of type I IFN during bacterial infection is enigmatic. Many intracellular bacteria induce type I IFNs during infection, but, rather than being protective for the host, type I IFNs enhance the host susceptibility to intracellular pathogens such as Listeria monocytogenes (53 , 54 ) , Salmonella Typhimurium (55 ), Chlamydia trachomatis ( 56 , 57) and Mycobacterium tuberculosis ( 58 -61). The mechanisms by which type I IFN signaling increases host susceptibility to bacterial infection is an active area of study and is not well defined. The phagolysosomal pathway is the front line defense against intracellular bacterial pathogensMacrophages are proficient in the internalization and destruction of bacteria, and in promoting innate immune responses (25). Following phagocytosis, a series of coordinated fusion and fission events with specific compartments of the endocytic pathway ultimately leads to the generation of a phagolysosome. The phagolysosome possesses potent microbicidal features, and has a lumen that constitutes a highly acidic, oxidative, and degradative environment.The acidification of the phagosome lumen is dependent on proton pumping by the V-ATPase, which is required for the optimal activity of lysosomal hydrolytic enzymes and interferes with bacterial growth by impairing the metabolism of some bacteria (25 , 62). The generation of ROS (reactive oxygen species) and RNS (reactive nitrogen species) by the NOX2 NADPH oxidase (63 , 64) and the inducible NOS2 nitric oxide synthase (65), respectively, are also important antimicrobial mechanisms of the phagolysosomal pathway.

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Section: Manipulation Of Host Sensing Pathways By Cytosolic Bacteriamentioning

confidence: 99%

Strategies Used by Bacteria to Grow in Macrophages

Mitchell

Chen

Portnoy

2017

Myeloid Cells in Health and Disease

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“…A later study noted that FTT0831c/FTL0325 mutants had reduced viability in laboratory medium, resulted in small colony phenotypes on agar, were larger and more spherical than wild-type cells, and had an irregular morphology with blebs near the bacterial midpoint and enlarged bacterial tips. Based on these abnormalities, the authors proposed that FTT0831c/FTL0325 acts as a structural protein to link the F. tularensis outer membrane to peptidoglycan (Robertson et al, 2014 ). The authors' results suggested that loss of FTT0831c/FTL0325 resulted in altered cell morphology and decreased viability, likely resulting in increased release or exposure of PAMPs, which may have explained the increased proinflammatory cytokine response previously observed.…”

Section: Outer Membrane Proteinsmentioning

confidence: 99%

From the Outside-In: The Francisella tularensis Envelope and Virulence

Rowe

Huntley

2015

Front. Cell. Infect. Microbiol.

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Francisella tularensis is a highly-infectious bacterium that causes the rapid, and often lethal disease, tularemia. Many studies have been performed to identify and characterize the virulence factors that F. tularensis uses to infect a wide variety of hosts and host cell types, evade immune defenses, and induce severe disease and death. This review focuses on the virulence factors that are present in the F. tularensis envelope, including capsule, LPS, outer membrane, periplasm, inner membrane, secretion systems, and various molecules in each of aforementioned sub-compartments. Whereas, no single bacterial molecule or molecular complex single-handedly controls F. tularensis virulence, we review here how diverse bacterial systems work in conjunction to subvert the immune system, attach to and invade host cells, alter phagosome/lysosome maturation pathways, replicate in host cells without being detected, inhibit apoptosis, and induce host cell death for bacterial release and infection of adjacent cells. Given that the F. tularensis envelope is the outermost layer of the bacterium, we highlight herein how many of these molecules directly interact with the host to promote infection and disease. These and future envelope studies are important to advance our collective understanding of F. tularensis virulence mechanisms and offer targets for future vaccine development efforts.

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“…FTL_0325, an OmpAlike protein, is an OMP that also contains four cysteines and has been reported to be required for in vitro and in vivo virulence in both LVS and SchuS4 (Mahawar et al, 2012;Robertson et al, 2014). FTL_0325 recently was shown to be a lipoprotein (Robertson et al, 2014), indicating that the first cysteine is a lipo-cysteine and the three remaining cysteines likely require FtDsbA isomerase activity for correct disulfide bond formation. Three additional OMPs also were identified as FtDsbA substrates, further validating the utility of our molecular trapping approach: Pal, Tul4-A, and Tul4-B (Table 1) (Huntley et al, 2007).…”

Section: Identification Of Ftdsba Substrates That Are Virulence Factorsmentioning

confidence: 99%

Identification of disulfide bond isomerase substrates reveals bacterial virulence factors

Ren

Champion

Huntley

2014

Molecular Microbiology

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Summary Bacterial pathogens are exposed to toxic molecules inside the host and require efficient systems to form and maintain correct disulfide bonds for protein stability and function. The intracellular pathogen Francisella tularensis encodes a disulfide bond formation protein ortholog, DsbA, which previously was reported to be required for infection of macrophages and mice. However, the molecular mechanisms by which F. tularensis DsbA contributes to virulence are unknown. Here, we demonstrate that F. tularensis DsbA is a bifunctional protein that oxidizes and, more importantly, isomerizes complex disulfide connectivity in substrates. A single amino acid in the conserved cis-proline loop of the DsbA thioredoxin domain was shown to modulate both isomerase activity and F. tularensis virulence. Trapping experiments in F. tularensis identified over 50 F. tularensis DsbA substrates, including outer membrane proteins, virulence factors, and many hypothetical proteins. Six of these hypothetical proteins were randomly selected and deleted, revealing two novel proteins, FTL_1548 and FTL_1709, which are required for F. tularensis virulence. We propose that the extreme virulence of F. tularensis is partially due to the bifunctional nature of DsbA, that many of the newly-identified substrates are required for virulence, and that the development of future DsbA inhibitors could have broad anti-bacterial implications.

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

Cited by 14 publications

References 50 publications

Strategies Used by Bacteria to Grow in Macrophages

Strategies Used by Bacteria to Grow in Macrophages

From the Outside-In: The Francisella tularensis Envelope and Virulence

Identification of disulfide bond isomerase substrates reveals bacterial virulence factors

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