Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.

/pdf/quorum-sensing-signal-response-systems-in-gram-negative-ncsir2ms1j.pdf

Quorum sensing signal–response systems in Gram-negative bacteria

Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies--the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.

Mitogen-activated protein kinases in innate immunity

Pseudomonas aeruginosa is a metabolically versatile bacterium that can cause a wide range of severe opportunistic infections in patients with serious underlying medical conditions. These infections are characterized by an intense neutrophilic response resulting in significant damage to host tissues and often exhibit resistance to antibiotics leading to mortality. Treatment of persistent infections is additionally hampered by adaptive resistance, due to the growth state of the bacterium in the patient including the microorganism's ability to grow as a biofilm. An array of P. aeruginosa virulence factors counteract host defences and can cause direct damage to host tissues or increase the bacterium's competitiveness. New prevention and treatment methods are urgently required to improve the outcome of patients with P. aeruginosa infections. This review describes the two main types of P. aeruginosa lung infections and provides an overview of the host response and how the genomic capacity of P. aeruginosa contributes to the pathogenesis and persistence of these infections.

Pseudomonas aeruginosa : new insights into pathogenesis and host defenses

Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. This may lead to the misclassification of tolerant strains as resistant, or vice versa, and result in ineffective treatments. In this Opinion article, we describe recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings. We propose a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the MIC together with a recently defined quantitative indicator of tolerance, the minimum duration for killing (MDK). Finally, we discuss genes that are associated with increased tolerance - the 'tolerome' - as targets for treating tolerant bacterial strains.

Distinguishing between resistance, tolerance and persistence to antibiotic treatment.

This chapter outlines the current understanding of host-pathogen interactions, illustrating the close evolutionary relationship between Salmonella and phagocytic cells. After oral ingestion, a proportion of Salmonella is able to withstand the acidic pH of the stomach and colonize the small intestine. Tumor necrosis factor alpha (TNF-α) also contributes toward the stimulation of oxidative responses by phagocytes and is crucial to the development of organized granulomas that contain bacteria within discrete foci in infected tissues. Extracellular and intracellular conditions that normally contribute to elimination of pathogens thus facilitate the adaptation of Salmonella to a physiological state that enables it to colonize macrophages and cause systemic disease. The subepithelial dome (SED) contains large numbers of phagocytes, many of which are CD11c+ dendritic cells (DCs); these are likely to be the first phagocytic cell type that Salmonella encounters following its translocation across the epithelial cell layer. Caspase-1- mediated apoptosis antagonizes clearance of the pathogen from the SED, and is important for colonization of the Peyer’s patches and bacterial dissemination to the lymph nodes and spleen. Antimicrobial activity is found in the cytosol of macrophages and the granules of neutrophils; delivery of these to Salmonella-containing vacuoles (SCVs) and the extracellular environment targets both intra- and extracellular Salmonella. Early vacuole maturation is characterized by delivery of vacuolar ATPase to the SCV and its subsequent acidification.

The Multiple Interactions between Salmonella and Phagocytes

Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide α-1,3-galactosyltransferase enzyme, which synthesizes Galα1-3Galβ1-4GlcNAc (αGal) and are thus tolerant to this self-expressed glycan epitope. Old World primates including humans, however, carry GGTA1 loss-of-function mutations and lack αGal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of αGal-specific immunity, which conferred resistance to αGal-expressing pathogens. Here we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of αGal-specific immunity. Rather, the absence of αGal from IgG-associated glycans increases IgG effector function, via a mechanism associated with enhanced IgG-Fc gamma receptor (FcγR) binding. The ensuing survival advantage against sepsis comes alongside a cost of earlier onset of reproductive senescence. Mathematical modeling of this trade-off shows that under conditions of high exposure to virulent pathogens, selective pressure can fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates towards humans.

/pdf/a-trade-off-between-resistance-to-infection-and-reproduction-1lvrikmbbm.pdf

Jessica A. Thompson

Papers

The Multiple Interactions between Salmonella and Phagocytes

A trade-off between resistance to infection and reproduction in primate evolution

Reconstructions of lateral slip on the northern death valley fault suggest a lower slip rate