Bacterial remodelling of the host epigenome: functional role and evolution of effectors methylating host histones

The modulation of the chromatin organization of eukaryotic cells plays an important role in regulating key cellular processes including host defence mechanisms against pathogens. Thus, to successfully survive in a host cell, a sophisticated bacterial strategy is the subversion of nuclear processes of the eukaryotic cell. Indeed, the number of bacterial proteins that target host chromatin to remodel the host epigenetic machinery is expanding. Some of the identified bacterial effectors that target the chromatin machinery are ‘eukaryotic‐like’ proteins as they mimic eukaryotic histone writers in carrying the same enzymatic activities. The best‐studied examples are the SET domain proteins that methylate histones to change the chromatin landscape. In this review, we will discuss SET domain proteins identified in the Legionella, Chlamydia and Bacillus genomes that encode enzymatic activities targeting host histones. Moreover, we discuss their possible origin as having evolved from prokaryotic ancestors or having been acquired from their eukaryotic hosts during their co‐evolution. The characterization of such bacterial effectors as modifiers of the host chromatin landscape is an exciting field of research as it elucidates new bacterial strategies to not only manipulate host functions through histone modifications but it may also identify new modifications of the mammalian host cells not known before.     

Epigenetic regulation of development and pathogenesis in fungal plant pathogens

Evidently, epigenetics is at forefront in explaining the mechanisms underlying the success of human pathogens and in the identification of pathogen‐induced modifications within host plants. However, there is a lack of studies highlighting the role of epigenetics in the modulation of the growth and pathogenicity of fungal plant pathogens. In this review, we attempt to highlight and discuss the role of epigenetics in the regulation of the growth and pathogenicity of fungal phytopathogens using Magnaporthe oryzae, a devastating fungal plant pathogen, as a model system. With the perspective of wide application in the understanding of the development, pathogenesis and control of other fungal pathogens, we attempt to provide a synthesized view of the epigenetic studies conducted on M. oryzae to date. First, we discuss the mechanisms of epigenetic modifications in M. oryzae and their impact on fungal development and pathogenicity. Second, we highlight the unexplored epigenetic mechanisms and areas of research that should be considered in the near future to construct a holistic view of epigenetic functioning in M. oryzae and other fungal plant pathogens. Importantly, the development of a complete understanding of the modulation of epigenetic regulation in fungal pathogens can help in the identification of target points to combat fungal pathogenesis.     

A curious case of resistance to a new encounter pathogen: myrtle rust in Australia

Resistance genes (R genes) in plants mediate a highly specific response to microbial pathogens, often culminating in localized cell death. Such resistance is generally pathogen race specific and believed to be the result of evolutionary selection pressure. Where a host and pathogen do not share an evolutionary history, specific resistance is expected to be absent or rare. Puccinia psidii, the causal agent of myrtle rust, was recently introduced to Australia, a continent rich in myrtaceous taxa. Responses within species to this new pathogen range from full susceptibility to resistance. Using the myrtle rust case study, we examine models to account for the presence of resistance to new encounter pathogens, such as the retention of ancient R genes through prolonged ‘trench warfare’, pairing of resistance gene products and the guarding of host integrity.     

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.     

Here,there, and everywhere: How pathogenic Escherichia coli sense and respond to gastrointestinal biogeography

Gastrointestinal (GI) pathogens enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC), and related mouse pathogen Citrobacter rodentium, are referred to as attaching and effacing (AE) pathogens for the lesions they form upon colonisation of the host epithelium. EPEC, EHEC, and C. rodentium are well known to use a type III secretion system to intimately attach to intestinal cells and secrete bacterial effectors to manipulate host cell processes. Less well known is the ability of AE pathogens to overcome significant physiological and microbial barriers and target specific gut niches for initial colonisation of the host epithelium. This review considers recent work highlighting the biogeography of the GI tract as it applies to colonisation by enteric pathogens, including environmental barriers to enteric infection, signals sensed by AE pathogens for navigation of the GI tract, and the tools AE pathogens use to respond to the changing host environment.     

Host cell death induced by the egress of intracellular <Emphasis Type="Italic">Plasmodium</Emphasis> parasites

Intracellular pathogens are known to inhibit host cell apoptosis efficiently to ensure their own survival. However, following replication within a cell, they typically need to egress in order to infect new cells. For a long time it was assumed that this happens by simply disrupting the host cell and in some cases, such as for Plasmodium-infected erythrocytes, this seems indeed to be true. However, recently it has been shown that in Plasmodium-infected hepatocytes, an ordered form of cell death is initiated. This cell death is parasite-dependent and can clearly be distinguished from apoptosis and necrosis. The key event, and point of no return, appears to be the rupture of the parasitophorous vacuole membrane (PVM). PVM disruption and host cell death depend on the activation of cysteine proteases. Whether these are of parasite or host cell origin seems to rely on the life cycle stage of the Plasmodium parasite and the corresponding host cell.     

Manipulation of the host cell death pathway by Shigella

Host cells deploy multiple defences against microbial infection. One prominent host defence mechanism, the death of infected cells, plays a pivotal role in clearing damaged cells, eliminating pathogens, removing replicative niches, exposing intracellular bacterial pathogens to extracellular immune surveillance and presenting bacteria‐derived antigens to the adaptive immune system. Although cell death can occur under either physiological or pathophysiological conditions, it acts as an innate defence mechanism against bacterial pathogens by limiting their persistent colonization. However, many bacterial pathogens, including Shigella, have evolved mechanisms that manipulate host cell death for their own benefit.     

A near death experience: Shigella manipulates host death machinery to silence innate immunity

Release of mitochondrial contents often triggers inflammation and cell death, and modulating this process can be advantageous to invading pathogens. In this issue of The EMBO Journal, Andree and colleagues reveal new findings that an intracellular bacterial pathogen exploits apoptotic machinery to suppress host immune signaling, yet avoids cell death. This study emphasizes the need to expand our understanding of the roles played by pro‐apoptotic proteins in non‐death scenarios.     

The recycling endosome and bacterial pathogens

Bacterial pathogens have developed a wide range of strategies to survive within human cells. A number of pathogens multiply in a vacuolar compartment, whereas others can rupture the vacuole and replicate in the host cytosol. A common theme among many bacterial pathogens is the use of specialised secretion systems to deliver effector proteins into the host cell. These effectors can manipulate the host's membrane trafficking pathways to remodel the vacuole into a replication‐permissive niche and prevent degradation. As master regulators of eukaryotic membrane traffic, Rab GTPases are principal targets of bacterial effectors. This review highlights the manipulation of Rab GTPases that regulate host recycling endocytosis by several bacterial pathogens, including Chlamydia pneumoniae, Chlamydia trachomatis, Shigella flexneri, Salmonella enterica serovar Typhimurium, Uropathogenic Escherichia coli, and Legionella pneumophila. Recycling endocytosis plays key roles in a variety of cellular aspects such as nutrient uptake, immunity, cell division, migration, and adhesion. Though much remains to be understood about the molecular basis and the biological relevance of bacterial pathogens exploiting Rab GTPases, current knowledge supports the notion that endocytic recycling Rab GTPases are differentially targeted to avoid degradation and support bacterial replication. Thus, future studies of the interactions between bacterial pathogens and host endocytic recycling pathways are poised to deepen our understanding of bacterial survival strategies.     

Histone modifications and chromatin remodeling during bacterial infections

The link between bacteria and host chromatin remodeling is an emerging topic. The exciting recent discoveries on bacterial impact on host epigenetics, as discussed in this Review, highlight yet another strategy used by bacterial pathogens to interfere with key cellular processes. The study of how pathogens provoke host chromatin changes will also provide new insights into host epigenetic regulation mechanisms.     

An extracellular Leptospira interrogans leucine‐rich repeat protein binds human E‐ and VE‐cadherins

Pathogenic Leptospira bacteria are the causative agents of leptospirosis, a zoonotic disease affecting animals and humans worldwide. These pathogenic species have the ability to rapidly cross host tissue barriers by a yet unknown mechanism. A comparative analysis of pathogens and saprophytes revealed a higher abundance of genes encoding proteins with leucine‐rich repeat (LRR) domains in the genomes of pathogens. In other bacterial pathogens, proteins with LRR domains have been shown to be involved in mediating host cell attachment and invasion. One protein from the pathogenic species Leptospira interrogans, LIC10831, has been previously analysed via X‐ray crystallography, with findings suggesting it may be an important bacterial adhesin. Herein we show that LIC10831 elicits an antibody response in infected animals, is actively secreted by the bacterium, and binds human E‐ and VE‐cadherins. These results provide biochemical and cellular evidences of LRR protein‐mediated host–pathogen interactions and identify a new multireceptor binding protein from this infectious Leptospira species.     

Caenorhabditis elegans as a model for intracellular pathogen infection

The genetically tractable nematode Caenorhabditis elegans is a convenient host for studies of pathogen infection. With the recent identification of two types of natural intracellular pathogens of C. elegans, this host now provides the opportunity to examine interactions and defence against intracellular pathogens in a whole‐animal model for infection. C. elegans is the natural host for a genus of microsporidia, which comprise a phylum of fungal‐related pathogens of widespread importance for agriculture and medicine. More recently, C. elegans has been shown to be a natural host for viruses related to the Nodaviridae family. Both microsporidian and viral pathogens infect the C. elegans intestine, which is composed of cells that share striking similarities to human intestinal epithelial cells. Because C. elegans nematodes are transparent, these infections provide a unique opportunity to visualize differentiated intestinal cells in vivo during the course of intracellular infection. Together, these two natural pathogens of C. elegans provide powerful systems in which to study microbial pathogenesis and host responses to intracellular infection.     

Selective inhibition of IFNG-induced autophagy by Mir155- and Mir31-responsive WNT5A and SHH signaling

Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31. Importantly, cellular levels of PP2A, a phosphatase, were regulated by Mir155 and Mir31 to fine-tune autophagy. Diminished expression of PP2A led to inhibition of GSK3B, thus facilitating the prolonged activation of WNT and SHH signaling pathways. Sustained WNT and SHH signaling effectuated the expression of anti-inflammatory lipoxygenases, which in tandem inhibited IFNG-induced JAK-STAT signaling and contributed to evasion of autophagy. Altogether, these results established a role for new host factors and inhibitory mechanisms employed by the pathogens to limit autophagy, which could be targeted for therapeutic interventions.     

Leishmania donovani Infection Causes Distinct Epigenetic DNA Methylation Changes in Host Macrophages

Infection of macrophages by the intracellular protozoan Leishmania leads to down-regulation of a number of macrophage innate host defense mechanisms, thereby allowing parasite survival and replication. The underlying molecular mechanisms involved remain largely unknown. In this study, we assessed epigenetic changes in macrophage DNA methylation in response to infection with L. donovani as a possible mechanism for Leishmania driven deactivation of host defense. We quantified and detected genome-wide changes of cytosine methylation status in the macrophage genome resulting from L. donovani infection. A high confidence set of 443 CpG sites was identified with changes in methylation that correlated with live L. donovani infection. These epigenetic changes affected genes that play a critical role in host defense such as the JAK/STAT signaling pathway and the MAPK signaling pathway. These results provide strong support for a new paradigm in host-pathogen responses, where upon infection the pathogen induces epigenetic changes in the host cell genome resulting in downregulation of innate immunity thereby enabling pathogen survival and replication. We therefore propose a model whereby Leishmania induced epigenetic changes result in permanent down regulation of host defense mechanisms to protect intracellular replication and survival of parasitic cells.     

Influence of Heterologously Expressed azurin from Pseudomonas aeruginosa on the Adhesion and Invasion of Pathogenic Bacteria to the Caco-2 Cell Line

This study proposed to investigate the effect of azurin on the major stages of pathogenesis (adhesion and invasion) of intestinal bacterial pathogens (Salmonella spp. and Escherichia coli) and epithelial pathogens (Staphylococcus aureus and Pseudomonas aeruginosa) on the human colorectal adenocarcinoma (Caco-2) cell line. Azurin protein was produced by cloning the azurin gene into pET21a and heterologous expression in E. coli BL21. The protein was purified using affinity chromatography and confirmed by Western blotting. The purified protein was evaluated by three experiments of adhesion and invasion assays, including exclusion, competition, and replacement. Azurin was observed to significantly inhibit the attachment and invasion of S. aureus, Salmonella spp., and E. coli, while no such inhibitory effects were observed on P. aeruginosa. In fact, the protein increased the adhesion of P. aeruginosa to the cell. In conclusion, our study proposes that azurin is a potential prophylactic or preventive helper candidate to inhibit the attachment and invasion of pathogenic bacteria to host cells and reduce the progression of the infection process. Our study also reveals the involvement of azurin in bacteria-host cell interactions, providing novel and important insights toward the elucidation of its biological function in this field. Thus, this study provides new opportunities to use azurin as an adjunct therapy against critical stages of infection by a wide range of pathogenic bacteria.

     

布鲁氏菌逃逸宿主的抗感染免疫机制

布鲁氏菌病是由布鲁氏菌引发的世界范围的人兽共患传染病。布鲁氏菌为兼性胞内寄生菌,无典型的毒力因子,但却有很强的致病性,常引发人和动物的慢性感染。逃逸宿主的抗感染免疫反应是慢性感染的先决条件,这种能力对于布鲁氏菌的毒力来说似乎也越来越关键。作为成功的致病性病原菌,布鲁氏菌采用"隐秘的"策略以逃避或抑制固有免疫、调节适应性免疫,从而在宿主细胞内建立长期的持续性感染。本文将围绕布鲁氏菌逃逸宿主的抗感染免疫的分子机制进行阐述,旨为阐明布鲁氏菌毒力的新见解,这很可能为布病的预防开辟新的途径。