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Itai Yanai

Publications and source records attributed to Itai Yanai.

7 recordsLinked to original sources
PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗
PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δagr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗
PubMed2002

The society of genes: networks of functional links between genes from comparative genomics.

BACKGROUND: Comparative genomics provides at least three methods beyond traditional sequence similarity for identifying functional links between genes: the examination of common phylogenetic distributions, the analysis of conserved proximity along the chromosomes of multiple genomes, and observations of fusions of genes into a multidomain gene in another organism. We have previously generated the links according to each of these methods individually for 43 known microbial genomes. Here we combine these results to construct networks of functional associations. RESULTS: We show that the functional networks obtained by applying these methods have different topologies and that the information they provide is largely additive. In particular, the combined networks of functional links contain an average of 57% of an organism's complete genetic complement, uncover substantial portions of known pathways, and suggest the function of previously unannotated genes. In addition, the combined networks are qualitatively different from the networks obtained using individual methods. They have a dominant cluster that contains approximately 80%-90% of the genes, independent of genome size, and the dominant clusters show the small world behavior expected of a biological system, with global connectivity that is nearly random, and local properties that are highly ordered. CONCLUSIONS: When the information on functional linkage provided by three emerging computational methods is combined, the integrated network uncovers large numbers of conserved pathways and identifies clusters of functionally related genes. It therefore shows considerable utility and promise as a tool for understanding genomic structure, and for guiding high throughput experimental investigations.

Chromosome Mapping↗
PubMed2002

Evolution of gene fusions: horizontal transfer versus independent events.

BACKGROUND: Gene fusions can be used as tools for functional prediction and also as evolutionary markers. Fused genes often show a scattered phyletic distribution, which suggests a role for processes other than vertical inheritance in their evolution. RESULTS: The evolutionary history of gene fusions was studied by phylogenetic analysis of the domains in the fused proteins and the orthologous domains that form stand-alone proteins. Clustering of fusion components from phylogenetically distant species was construed as evidence of dissemination of the fused genes by horizontal transfer. Of the 51 examined gene fusions that are represented in at least two of the three primary kingdoms (Bacteria, Archaea and Eukaryota), 31 were most probably disseminated by cross-kingdom horizontal gene transfer, whereas 14 appeared to have evolved independently in different kingdoms and two were probably inherited from the common ancestor of modern life forms. On many occasions, the evolutionary scenario also involves one or more secondary fissions of the fusion gene. For approximately half of the fusions, stand-alone forms of the fusion components are encoded by juxtaposed genes, which are known or predicted to belong to the same operon in some of the prokaryotic genomes. This indicates that evolution of gene fusions often, if not always, involves an intermediate stage, during which the future fusion components exist as juxtaposed and co-regulated, but still distinct, genes within operons. CONCLUSION: These findings suggest a major role for horizontal transfer of gene fusions in the evolution of protein-domain architectures, but also indicate that independent fusions of the same pair of domains in distant species is not uncommon, which suggests positive selection for the multidomain architectures.

DNA, Archaeal↗
PubMed2002

Predictome: a database of putative functional links between proteins.

The current deluge of genomic sequences has spawned the creation of tools capable of making sense of the data. Computational and high-throughput experimental methods for generating links between proteins have recently been emerging. These methods effectively act as hypothesis machines, allowing researchers to screen large sets of data to detect interesting patterns that can then be studied in greater detail. Although the potential use of these putative links in predicting gene function has been demonstrated, a central repository for all such links for many genomes would maximize their usefulness. Here we present Predictome, a database of predicted links between the proteins of 44 genomes based on the implementation of three computational methods--chromosomal proximity, phylogenetic profiling and domain fusion--and large-scale experimental screenings of protein-protein interaction data. The combination of data from various predictive methods in one database allows for their comparison with each other, as well as visualization of their correlation with known pathway information. As a repository for such data, Predictome is an ongoing resource for the community, providing functional relationships among proteins as new genomic data emerges. Predictome is available at http://predictome.bu.edu.

Animals↗
PubMed2002

Identifying functional links between genes using conserved chromosomal proximity.

Conservation of proximity of a pair of genes across multiple genomes generally indicates that their functions could be linked. Here, we present a systematic evaluation using 42 complete microbial genomes from 25 phylogenetic groups to test the reliability of this observation in predicting function for genes. We find a relationship between the number of phylogenetic groups in which a gene pair is proximate and the probability that the pair belongs to a common pathway. Our method produces 1586 links between ortholog families substantiated by observed proximity in genomes representing at least three phylogenetic groups. Of the pairs annotated in the KEGG database, 80% are in the same biological pathway in KEGG.

Chromosome Mapping↗