Tales from the underground: molecular

Colonization of the rhizosphere by micro‐organisms results in modifications in plant growth and development. This review examines the mechanisms involved in growth promotion by plant growth‐promoting rhizobacteria which are divided into indirect and direct effects. Direct effects include enhanced provision of nutrients and the production of phytohormones. Indirect effects involve aspects of biological control: the production of antibiotics and iron‐chelating siderophores and the induction of plant resistance mechanisms. The study of the molecular basis of growth promotion demonstrated the important role of bacterial traits (motility, adhesion and growth rate) for colonization. New research areas emerge from the discovery that molecular signalling occurs through plant perception of eubacterial flagellins. Recent perspectives in the molecular genetics of cross‐talking mechanisms governing plant–rhizobacteria interactions are also discussed.     

Molecular communication in the rhizosphere

This paper will exemplify molecular communications in the rhizosphere, especially between plants and bacteria, and between bacteria and bacteria. More specifically, we describe signalling pathways that allow bacteria to sense a wide diversity of plant signals, plants to respond to bacterial infection, and bacteria to coordinate gene expression at population and community level. Thereafter, we focus on mechanisms evolved by bacteria and plants to disturb bacterial signalling, and by bacteria to modulate hormonal signalling in plants. Finally, the dynamics of signal exchange and its biological significance we elaborate on the cases of Rhizobium symbiosis and Agrobacterium pathogenesis.     

Quorum sensing and signal interference: diverse implications

Quorum sensing (QS) is a community genetic regulation mechanism that controls microbiological functions of medical, agricultural and industrial importance. Discovery of microbial QS signals and the signalling mechanisms led to identification of numerous enzymatic and non-enzymatic signal interference mechanisms that quench microbial QS signalling. Evidence is accumulating that such signal interference mechanisms can be developed as promising approaches to control microbial infection and biofilm formation. In addition, these mechanisms exist not only in microorganisms but also in the host organisms of bacterial pathogens, highlighting their potential implications in microbial ecology and in host-pathogen interactions. Investigation of QS and signal interference mechanisms might significantly broaden the scope of research in microbiology.     

The bacterial second messenger c-di-GMP: mechanisms of signalling

Cyclic-di-GMP (c-di-GMP) regulates many important bacterial processes. Freely diffusible intracellular c-di-GMP is determined by the action of metabolizing enzymes that allow integration of numerous input signals. c-di-GMP specifically regulates multiple cellular processes by binding to diverse target molecules. This review highlights important questions in research into the mechanisms of c-di-GMP signalling and its role in bacterial physiology.     

Spatial organization in bacterial chemotaxis

Spatial organization of signalling is not an exclusive property of eukaryotic cells. Despite the fact that bacterial signalling pathways are generally simpler than those in eukaryotes, there are several well‐documented examples of higher‐order intracellular signalling structures in bacteria. One of the most prominent and best‐characterized structures is formed by proteins that control bacterial chemotaxis. Signals in chemotaxis are processed by ordered arrays, or clusters, of receptors and associated proteins, which amplify and integrate chemotactic stimuli in a highly cooperative manner. Receptor clusters further serve to scaffold protein interactions, enhancing the efficiency and specificity of the pathway reactions and preventing the formation of signalling gradients through the cell body. Moreover, clustering can also ensure spatial separation of multiple chemotaxis systems in one bacterium. Assembly of receptor clusters appears to be a stochastic process, but bacteria evolved mechanisms to ensure optimal cluster distribution along the cell body for partitioning to daughter cells at division.     

Sensing of bacteria: NOD a lonely job

Recognition of bacteria by the vertebrate innate immune system relies on detection of invariant molecules by specialized receptors. The view is emerging that activation of both Toll-like receptors (TLRs) and Nod-like receptors (NLRs) by different bacterial agonists is important in order to mount an inflammatory response in the host. Priming of cells with peptidoglycan and products that are sensed by cytosolic-localized members of the NLR family have a synergistic effect on TLR signalling and vice versa. Currently, the underlying molecular mechanisms of this cross-talk between NLR and TLR signalling are beginning to emerge. These reveal that the two sensing-systems are non-redundant in bacterial recognition and that their cross-talk plays an important role in immunological homeostasis.     

Listening in on bacteria: acyl-homoserine lactone signalling

Bacterial cell-to-cell signalling has emerged as a new area in microbiology. Individual bacterial cells communicate with each other and co-ordinate group activities. Although a lot of detail is known about the mechanisms of a few well-characterized bacterial communication systems, other systems have been discovered only recently. Bacterial intercellular communication has become a target for the development of new anti-virulence drugs.     

Opinion: Bacterial toxins and cancer--a case to answer?

Since the discovery that Helicobacter pylori infection leads to gastric cancer, other chronic bacterial infections have been shown to cause cancer. The bacterial and host molecular mechanisms remain unclear. However, many bacteria that cause persistent infections produce toxins that specifically disrupt cellular signalling to perturb the regulation of cell growth or to induce inflammation. Other bacterial toxins directly damage DNA. Such toxins mimic carcinogens and tumour promoters and might represent a paradigm for bacterially induced carcinogenesis.     

Ubiquitylation and autophagy in the control of bacterial infections and related inflammatory responses

The ubiquitin proteasome system and autophagy constitute key signalling pathways in the host response to infection. The identification of adaptors linking the two pathways has prompted a re-examination of the latter's involvement in inflammatory reactions and the clearance of bacteria. The ubiquitin-autophagy pathway is a preferred target for effectors from pathogens that seek to exploit and evade the host defence mechanisms. A number of new players and signalling nodes have recently been identified. Here, we discuss these new insights into the host's control of bacterial infection.     

Modulation of the host innate immune and inflammatory response by translocated bacterial proteins

Bacterial secretion systems play a central role in interfering with host inflammatory responses to promote replication in tissue sites. Many intracellular bacteria utilize secretion systems to promote their uptake and survival within host cells. An intracellular niche can help bacteria avoid killing by phagocytic cells, and may limit host sensing of bacterial components. Secretion systems can also play an important role in limiting host sensing of bacteria by translocating proteins that disrupt host immune signalling pathways. Extracellular bacteria, on the other hand, utilize secretion systems to prevent uptake by host cells and maintain an extracellular niche. Secretion systems, in this case, limit sensing and inflammatory signalling which can occur as bacteria replicate and release bacterial products in the extracellular space. In this review, we will cover the common mechanisms used by intracellular and extracellular bacteria to modulate innate immune and inflammatory signalling pathways, with a focus on translocated proteins of the type III and type IV secretion systems.     

Priming for enhanced defence responses by specific inhibition of the Arabidopsis response to coronatine

The priming agent β-aminobutyric acid (BABA) is known to enhance Arabidopsis resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 by potentiating salicylic acid (SA) defence signalling, notably PR1 expression. The molecular mechanisms underlying this phenomenon remain unknown. A genome-wide microarray analysis of BABA priming during Pst DC3000 infection revealed direct and primed up-regulation of genes that are responsive to SA, the SA analogue benzothiadiazole and pathogens. In addition, BABA was found to inhibit the Arabidopsis response to the bacterial effector coronatine (COR). COR is known to promote bacterial virulence by inducing the jasmonic acid (JA) response to antagonize SA signalling activation. BABA specifically repressed the JA response induced by COR without affecting other plant JA responses. This repression was largely SA-independent, suggesting that it is not caused by negative cross-talk between SA and JA signalling cascades. Treatment with relatively high concentrations of purified COR counteracted BABA inhibition. Under these conditions, BABA failed to protect Arabidopsis against Pst DC3000. BABA did not induce priming and resistance in plants inoculated with a COR-deficient strain of Pst DC3000 or in the COR-insensitive mutant coi1-16. In addition, BABA blocked the COR-dependent re-opening of stomata during Pst DC3000 infection. Our data suggest that BABA primes for enhanced resistance to Pst DC3000 by interfering with the bacterial suppression of Arabidopsis SA-dependent defences. This study also suggests the existence of a signalling node that distinguishes COR from other JA responses.     

Pathogen-induced apoptosis of macrophages: a common end for different pathogenic strategies

Microbe–macrophage interactions play a central role in the pathogenesis of many infections. Several bacterial pathogens induce apoptosis specifically in macrophages, but the mechanisms by which it occurs differ, and the resulting pathology can take different courses. Macrophage death caused by Shigella flexneri and Salmonella spp. has been shown to result in the release of pro-inflammatory cytokines. Conversely, Yersinia spp. induce apoptosis by suppressing the signalling pathways that lead to the production of tumour necrosis factor (TNF)-α, a cytokine essential for the control of this infection. It is likely that there are a variety of reasons why macrophages are particularly susceptible to pathogen-induced apoptosis. One reason may be the expression of surface receptors that recognize highly conserved bacterial components, such as lipopolysaccharide (LPS) and bacterial lipoproteins (BLPs). These receptors have recently been shown to activate pro-apoptotic signalling pathways. The roles of macrophage apoptosis in different disease processes are discussed.     

Bacterial signal transduction network in a genomic perspective

Bacterial signalling network includes an array of numerous interacting components that monitor environmental and intracellular parameters and effect cellular response to changes in these parameters. The complexity of bacterial signalling systems makes comparative genome analysis a particularly valuable tool for their studies. Comparative studies revealed certain general trends in the organization of diverse signalling systems. These include (i) modular structure of signalling proteins; (ii) common organization of signalling components with the flow of information from N-terminal sensory domains to the C-terminal transmitter or signal output domains (N-to-C flow); (iii) use of common conserved sensory domains by different membrane receptors; (iv) ability of some organisms to respond to one environmental signal by activating several regulatory circuits; (v) abundance of intracellular signalling proteins, typically consisting of a PAS or GAF sensor domains and various output domains; (vi) importance of secondary messengers, cAMP and cyclic diguanylate; and (vii) crosstalk between components of different signalling pathways. Experimental characterization of the novel domains and domain combinations would be needed for achieving a better understanding of the mechanisms of signalling response and the intracellular hierarchy of different signalling pathways.     

How bacteria could cause cancer: one step at a time

Helicobacter pylori highlighted the potential for bacteria to cause cancer. It is becoming clear that chronic infection with other bacteria, notably Salmonella typhi, can also facilitate tumour development. Infections caused by several bacteria (e.g. Bartonella spp., Lawsonia intracellularis and Citrobacter rodentium) can induce cellular proliferation that can be reversed by antibiotic treatment. Other chronic bacterial infections have the effect of blocking apoptosis. However, the underlying cellular mechanisms are far from clear. Conversely, several bacterial toxins interfere with cellular signalling mechanisms in a way that is characteristic of tumour promoters. These include Pasteurella multocida toxin, which uniquely acts as a mitogen, and Escherichia coli cytotoxic necrotizing factor, which activates Rho family signalling. This leads to activation of COX2, which is involved in several stages of tumour development, including inhibition of apoptosis. Such toxins could provide valuable models for bacterial involvement in cancer, but more significantly they could play a direct role in cancer causation and progression.     

Diffusible signal factor‐dependent quorum sensing in pathogenic bacteria and its exploitation for disease control

Cell‐to‐cell signals of the diffusible signal factor (DSF) family are cis‐2‐unsaturated fatty acids of differing chain length and branching pattern. DSF signalling has been described in diverse bacteria to include plant and human pathogens where it acts to regulate functions such as biofilm formation, antibiotic tolerance and the production of virulence factors. DSF family signals can also participate in interspecies signalling with other bacteria and interkingdom signalling such as with the yeast Candida albicans. Interference with DSF signalling may afford new opportunities for the control of bacterial disease. Such strategies will depend in part on detailed knowledge of the molecular mechanisms underlying the processes of signal synthesis, perception and turnover. Here, I review both recent progress in understanding DSF signalling at the molecular level and prospects for translating this knowledge into approaches for disease control.     

Diversity of bacterial manipulation of the host ubiquitin pathways

Ubiquitination is generally considered as a eukaryotic protein modification, which is catalysed by a three‐enzyme cascade and is reversed by deubiquitinating enzymes. Ubiquitination directs protein degradation and regulates cell signalling, thereby plays key roles in many cellular processes including immune response, vesicle trafficking and cell cycle. Bacterial pathogens inject a series of virulent proteins, named effectors, into the host cells. Increasing evidence suggests that many effectors hijack the host ubiquitin pathways to benefit bacterial infection. This review summarizes the known functions and mechanisms of effectors from human bacterial pathogens including enteropathogenic Escherichia coli, Salmonella, Shigella, Chlamydia and Legionella, highlighting the diversity in their mechanisms for manipulating the host ubiquitin pathways. Many effectors adopt the molecular mimicry strategy to harbour similar structures or functional motifs with those of the host E3 ligases and deubiquitinases. On the other hand, a few of effectors evolve novel structures or new enzymatic activities to modulate various steps of the host ubiquitin pathways. The diversity in the mechanisms enhances the efficient exploitation of the host ubiquitination signalling by bacteria.     

The Salmonella pathogenicity island 1 secretion system directs cellular cholesterol redistribution during mammalian cell entry and intracellular trafficking

The bacterial pathogen Salmonella triggers its own uptake into non-phagocytic mammalian cells. Entry is induced by the delivery of bacterial effector pro-teins that subvert signalling and promote cytoskeletal rearrangement, although the molecular mechanisms that co-ordinate initial pathogen-host cell recognition remain poorly characterized. Here we show that cholesterol is essential for Salmonella uptake. Depletion and chelation of plasma membrane cholesterol specifically inhibited bacterial internalization but not adherence. Cholesterol accumulated at bacterial entry sites in cultured cells, and was retained by Salmonella -containing vacuoles following pathogen internalization. Cellular cholesterol redistribution required bacterial effector protein delivery mediated by the Salmonella pathogenicity island (SPI) 1 type III secretion system, but was independent of the SPI2-encoded system.