Importance of Branched-Chain Amino Acid Utilization in Francisella Intracellular Adaptation

Gesbert, Gaël; Ramond, Elodie; Tros, Fabiola; Dairou, Julien; Frapy, Eric; Barel, Monique; Charbit, Alain

doi:10.1128/iai.02579-14

Cited by 38 publications

(50 citation statements)

References 49 publications

(65 reference statements)

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“…Accumulating evidence indicates that the nutrient composition of the cytosol is a critical denominator, since deficiencies in metabolic pathways render intracytosolic bacteria incapable of intracellular replication (15)(16)(17)(18)(67)(68)(69). In addition, evidence indicates that primary phagocytic cells, such as BMDM, generally control infection caused even by pathogens that replicate in the cytosol better than most macrophagederived cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it was hypothesized that bacteria which successfully replicate in the cytosol harbor a metabolic machinery that is adapted to this niche in order to utilize available nutrients (14). However, there is accumulating evidence that the metabolic requirements may be similar for bacteria residing within the eukaryotic cytosol and bacteria residing extracellularly (15)(16)(17)(18)(19), thus indicating that modulation of the cytosolic composition, e.g., by deprivation of the availability of metabolites, may be an important factor to control replication of intracellular bacteria. To add further complexity, there is recent evidence that manipulation of autophagy is used as a means by pathogens to acquire energy and nutrients.…”

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Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

et al. 2015

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bCertain intracellular bacteria use the host cell cytosol as the replicative niche. Although it has been hypothesized that the successful exploitation of this compartment requires a unique metabolic adaptation, supportive evidence is lacking. For Francisella tularensis, many genes of the Francisella pathogenicity island (FPI) are essential for intracellular growth, and therefore, FPI mutants are useful tools for understanding the prerequisites of intracytosolic replication. We compared the growth of bacteria taken up by phagocytic or nonphagocytic cells with that of bacteria microinjected directly into the host cytosol, using the live vaccine strain (LVS) of F. tularensis; five selected FPI mutants thereof, i.e., ⌬iglA, ⌬iglC¸⌬iglG, ⌬iglI, and ⌬pdpE strains; and Listeria monocytogenes. After uptake in bone marrow-derived macrophages (BMDM), ASC ؊/؊ BMDM, MyD88 ؊/؊ BMDM, J774 cells, or HeLa cells, LVS, ⌬pdpE and ⌬iglG mutants, and L. monocytogenes replicated efficiently in all five cell types, whereas the ⌬iglA and ⌬iglC mutants showed no replication. After microinjection, all 7 strains showed effective replication in J774 macrophages, ASC ؊/؊ BMDM, and HeLa cells. In contrast to the rapid replication in other cell types, L. monocytogenes showed no replication in MyD88 ؊/؊ BMDM and LVS showed no replication in either BMDM or MyD88 ؊/؊ BMDM after microinjection. Our data suggest that the mechanisms of bacterial uptake as well as the permissiveness of the cytosolic compartment per se are important factors for the intracytosolic replication. Notably, none of the investigated FPI proteins was found to be essential for intracytosolic replication after microinjection. Bacteria and other microbes have developed an ability to invade host cells and use them as a principal habitat for replication. These so-called intracellular pathogens are able to trigger their uptake by mammalian cells, by phagocytosis when the host cells are professional phagocytes, e.g., monocytes or macrophages, or by triggered phagocytosis in the case of nonprofessional phagocytic host cells, such as epithelial or endothelial cells, hepatocytes, and fibroblasts (1, 2). After internalization, virulence factors produced by the intracellular pathogen modulate the intracellular environment to facilitate microbial survival (3, 4). For protection against intracellularly located microorganisms, the immune system is dependent on pattern recognition receptors (PRR) that identify conserved microbial components (5). The best-characterized family of PRR is the one of Toll-like receptors (TLR), a group of integral membrane proteins that recognize microbial components, such as lipopolysaccharide, bacterial lipoprotein, and CpG DNA (6, 7). Triggering of TLR leads to rapid initiation of an antimicrobial proinflammatory response (8, 9). These innate defense mechanisms are normally sufficient to mediate the eradication of phagocytosed extracellular pathogens but not to control those capable of intracellular replication.Many intracellular bacteria, e.g., Mycobacterium,...

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Section: Discussionmentioning

confidence: 99%

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Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

et al. 2015

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“…91 Francisella tularensis depends on amino acid importers for adaptation to intracellular life. 92 Transcriptome analysis shows that transporters of amino acids like glutamine and proline get upregulated in the uropathogenic E. coli during urinary tract infection. 93 Therefore, there is certainly an overlap in the functions of peptide transporters and amino acid transporters.…”

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Bacterial peptide transporters: Messengers of nutrition to virulence

2016

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Bacteria possess numerous peptide transporters for importing peptides as nutrients. However, these peptide transporters are now consistently reported to play a role in the virulence of various bacterial pathogens. Their ability to transport peptides has implications in antibacterial therapy as well. Therefore, it would be instrumental to have complete knowledge about the role of peptide transporters in mediating this cross connection between metabolism and pathogenesis. Studies on various peptide transporters in bacterial pathogens have improved our understanding of this field. In this review, we have given an overview of the functioning of bacterial peptide transporters and their contribution in virulence of major bacterial pathogens.

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“…The majority of genes involved in purine biosynthesis and transporters did not replicate to any detectable level in either cell type, reiterating the known dependence on purine biosynthesis and dependence on host nutrients for intracellular growth and virulence (7,19,31,32). Mutants that grew to intermediate levels in both cell types included those involved in essential bacterial processes, carbon metabolism and DNA replication and repair.…”

Section: Discussionmentioning

confidence: 99%

Identifying Francisella tularensis Genes Required for Growth in Host Cells

et al. 2015

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c Francisella tularensis is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of F. tularensis virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes. FTT_0924, a gene of unknown function but highly conserved among Francisella species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines. FTT_0924 was required for full Schu S4 virulence in a murine pulmonary infection model. The ⌬FTT_0924 mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that FTT_0924 is required for resisting osmotic stress. The ⌬FTT_0924 mutant was also significantly more sensitive to ␤-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that FTT_0924 is required for maintaining peptidoglycan integrity and virulence.

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Importance of Branched-Chain Amino Acid Utilization in Francisella Intracellular Adaptation

Cited by 38 publications

References 49 publications

Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

Microinjection of Francisella tularensis and Listeria monocytogenes Reveals the Importance of Bacterial and Host Factors for Successful Replication

Bacterial peptide transporters: Messengers of nutrition to virulence

Identifying Francisella tularensis Genes Required for Growth in Host Cells

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