A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella

Ledvina, Hannah E.; Kelly, Katherine A.; Eshraghi, Aria; Plemel, Rachael L.; Peterson, S. Brook; Lee, Brian; Steele, Shaun; Adler, Marlen; Kawula, Thomas H.; Merz, Alexey J.; Skerrett, Shawn J.; Celli, Jean; Mougous, Joseph D.

doi:10.1016/j.chom.2018.07.003

Cited by 57 publications

(72 citation statements)

References 70 publications

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“…Interestingly, the latter study also identified putative effector proteins encoded outside of the FPI for F. novicida, including OpiA. In a follow up study, this protein was shown to possess phosphatidylinositol 3-kinase-activity, alter phagosomal maturation, and, thereby, promote intracellular growth of F. novicida (Ledvina et al, 2018).…”

Section: Putative T6ss Effectorsmentioning

confidence: 88%

Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach

2020

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Pan-genome analysis is a powerful method to explore genomic heterogeneity and diversity of bacterial species. Here we present a pan-genome analysis of the genus Francisella, comprising a dataset of 63 genomes and encompassing clinical as well as environmental isolates from distinct geographic locations. To determine the evolutionary relationship within the genus, we performed phylogenetic whole-genome studies utilizing the average nucleotide identity, average amino acid identity, core genes and non-recombinant loci markers. Based on the analyses, the phylogenetic trees obtained identified two distinct clades, A and B and a diverse cluster designated C. The sizes of the pan-, core-, cloud-, and shell-genomes of Francisella were estimated and compared to those of two other facultative intracellular pathogens, Legionella and Piscirickettsia. Francisella had the smallest core-genome, 692 genes, compared to 886 and 1,732 genes for Legionella and Piscirickettsia respectively, while the pangenome of Legionella was more than twice the size of that of the other two genera. Also, the composition of the Francisella Type VI secretion system (T6SS) was analyzed. Distinct differences in the gene content of the T6SS were identified. In silico approaches performed to identify putative substrates of these systems revealed potential effectors targeting the cell wall, inner membrane, cellular nucleic acids as well as proteins, thus constituting attractive targets for site-directed mutagenesis. The comparative analysis performed here provides a comprehensive basis for the assessment of the phylogenomic relationship of members of the genus Francisella and for the identification of putative T6SS virulence traits.

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Section: Putative T6ss Effectorsmentioning

confidence: 88%

Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach

2020

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“…As part of an effort to determine the function of a Francisella effector, OpiA, LegA5 was found to possess PI 3-kinase activity. LegA5 contains two motifs, DXHXXN and IDH, separated by 14 amino acids that are characteristic of the catalytic and activation loops of PI 3-kinases (and PI 4-kinases) [52]. PI(3)P has been shown to accumulate on the LCV early during infection in a manner independent of effector protein translocation [12].…”

Section: Pneumophila Converts the Phagosome To A Pi(4)p-rich Vacuomentioning

confidence: 99%

Exploitation of Phosphoinositides by the Intracellular Pathogen,Legionella pneumophila

Pike¹,

Noll²,

Neunuebel³

2020

Pathogenic Bacteria

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Manipulation of host phosphoinositide lipids has emerged as a key survival strategy utilized by pathogenic bacteria to establish and maintain a replication-permissive compartment within eukaryotic host cells. The human pathogen, Legionella pneumophila, infects and proliferates within the lung's innate immune cells causing severe pneumonia termed Legionnaires' disease. This pathogen has evolved strategies to manipulate specific host components to construct its intracellular niche termed the Legionella-containing vacuole (LCV). Paramount to LCV biogenesis and maintenance is the spatiotemporal regulation of phosphoinositides, important eukaryotic lipids involved in cell signaling and membrane trafficking. Through a specialized secretion system, L. pneumophila translocates multiple proteins that target phosphoinositides in order to escape endolysosomal degradation. By specifically binding phosphoinositides, these proteins can anchor to the cytosolic surface of the LCV or onto specific host membrane compartments, to ultimately stimulate or inhibit encounters with host organelles. Here, we describe the bacterial proteins involved in binding and/or altering host phosphoinositide dynamics to support intracellular survival of L. pneumophila.

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“…By promoting or preventing cytoskeleton re-arrangements through the action of specific effectors that target actin or tubulin, the T6SSs of Vibrio cholerae, Aeromonas hydrophila, and Pseudomonas aeruginosa disable phagocytic cells or stimulate internalization into non-phagocytic cells (21,22,(24)(25)(26). Other T6SSs have been demonstrated to manipulate host cells, although the molecular determinants are not yet entirely understood (27)(28)(29)(30). However, T6SS gene clusters are widespread in Gram-negative bacterial genomes, and not restricted to pathogens (10).…”

Section: Type VI Secretion System Effectorsmentioning

confidence: 99%

Structure and Activity of the Type VI Secretion System

Cherrak

Flaugnatti

Durand

et al. 2019

Protein Secretion in Bacteria

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The Type VI secretion system (T6SS) is a multiprotein machine that uses a spring-like mechanism to inject effectors into target cells. The injection apparatus is composed of a baseplate on which is built a contractile tail tube/sheath complex. The inner tube, topped by the spike complex, is propelled outside of the cell by the contraction of the sheath. The injection system is anchored to the cell envelope and oriented towards the cell exterior by a trans-envelope complex. Effectors delivered by the T6SS are loaded within the inner tube or on the spike complex, and can target prokaryotic and/or eukaryotic cells. Here, we summarize the structure, assembly and mechanism of action of the T6SS. We also review the function of effectors and their mode of recruitment and delivery.

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A Phosphatidylinositol 3-Kinase Effector Alters Phagosomal Maturation to Promote Intracellular Growth of Francisella

Cited by 57 publications

References 70 publications

Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach

Exploring the Diversity Within the Genus Francisella – An Integrated Pan-Genome and Genome-Mining Approach

Exploitation of Phosphoinositides by the Intracellular Pathogen,Legionella pneumophila

Structure and Activity of the Type VI Secretion System

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