Molecular interactions between bacterial symbionts and their hosts

Symbiotic bacteria are important in animal hosts, but have been largely overlooked as they have proved difficult to culture in the laboratory. Approaches such as comparative genomics and real-time PCR have provided insights into the molecular mechanisms that underpin symbiont-host interactions. Studies on the heritable symbionts of insects have yielded valuable information about how bacteria infect host cells, avoid immune responses, and manipulate host physiology. Furthermore, some symbionts use many of the same mechanisms as pathogens to infect hosts and evade immune responses. Here we discuss what is currently known about the interactions between bacterial symbionts and their hosts.     

Eukaryotic glycosyltransferases: cysteines and disulfides

Significant progress has been made in discovering and cloning a host of eukaryotic glycosyltransferases, demonstrating the intricacy and complexity of protein and lipid glycosylation. The availability of their predicted amino acid sequences extended our insights into the structure/function aspects of this family of proteins. However, our knowledge of their three-dimensional structures and how structure gives rise to substrate binding and specificity is still limited. Glycosyltransferase X-ray crystal structures have begun to provide significant information on a limited number of enzymes. To date, only three eukaryotic glycosyltransferase crystal structures have been solved, and all of them are for enzymes that utilize a UDP-sugar. One of the important structural elements of a protein is its disulfide bonds. These covalent interactions place conformational constraints on the overall protein structure,providing some important structural information. In this letter, we outline our current understanding of the free Cys residues and disulfide bonds in eukaryotic glycosyltransferases and discuss some of the important outcomes of these findings.     

Ergosterol,an orphan fungal microbe‐associated molecular pattern (MAMP)

Fungal pathogens continue to pose a significant threat to crop production and food supply. The early stages of plant–fungus interactions are mostly mediated by microbe‐associated molecular pattern (MAMP) molecules, perceived by plant pattern recognition receptors (PRRs). Currently, the identified fungal MAMP molecules include chitin, chitosan, β‐glucans, elicitins and ergosterol. Although the molecular battles between host plants and infecting fungal phytopathogens have been studied extensively, many aspects still need to be investigated to obtain a holistic understanding of the intrinsic mechanisms, which is paramount in combating fungal plant diseases. Here, an overview is given of the most recent findings concerning an ‘orphan’ fungal MAMP molecule, ergosterol, and we present what is currently known from a synopsis of different genes, proteins and metabolites found to play key roles in induced immune responses in plant–fungus interactions. Clearly, integrative investigations are still needed to provide a comprehensive systems‐based understanding of the dynamics associated with molecular mechanisms in plant–ergosterol interactions and associated host responses.     

How parasite interaction strategies alter virulence evolution in multi‐parasite communities

The majority of organisms host multiple parasite species, each of which can interact with hosts and competitors through a diverse range of direct and indirect mechanisms. These within‐host interactions can directly alter the mortality rate of coinfected hosts and alter the evolution of virulence (parasite‐induced host mortality). Yet we still know little about how within‐host interactions affect the evolution of parasite virulence in multi‐parasite communities. Here, we modeled the virulence evolution of two coinfecting parasites in a host population in which parasites interacted through cross immunity, immune suppression, immunopathology, or spite. We show (1) that these within‐host interactions have different effects on virulence evolution when all parasites interact with each other in the same way versus when coinfecting parasites have unique interaction strategies, (2) that these interactions cause the evolution of lower virulence in some hosts, and higher virulence in other hosts, depending on the hosts infection status, and (3) that for cross immunity and spite, whether parasites increase or decrease the evolutionarily stable virulence in coinfected hosts depended on interaction strength. These results improve our understanding of virulence evolution in complex parasite communities, and show that virulence evolution must be understood at the community scale.     

Viral proteomics: global evaluation of viruses and their interaction with the host

Viruses constantly adapt to and modulate the host environment during replication and propagation. Both DNA and RNA viruses encode multifunctional proteins that interact with and modify host cell proteins. While viral genomes were the first complete sequences known, the corresponding proteomes are only now elucidated, with some surprising results. Even more daunting is the task to globally monitor the impact of viral infection on the proteome of the host cell and many technical hurdles must still be overcome in order to facilitate robust and reproducible measurements. Further complicating the picture is the dynamic nature of proteins, including post-translational modifications, enzymatic cleavage and activation or destruction by proteolytic events. Nevertheless, several promising studies have been published using high-throughput methods directly measuring protein abundance. Particularly, quantitative or semiquantitative mass spectrometry-based analysis of viral and cellular proteomes are now being used to characterize viruses and their host interaction. In addition, the full set of interactions between viral and host proteins, the interactome, is beginning to emerge, with often unexpected interactions that need to be carefully validated. In this review, we will discuss two major areas of viral proteomics: first, virion proteomics (such as the protein characterization of viral particles) and second, proteoviromics, including the viral protein interactomics and the quantitative analysis of host cell proteome during viral infection.     

Photorhabdus: towards a functional genomic analysis of a symbiont and pathogen

Pathogenicity and symbiosis are central to bacteria-host interactions. Although several human pathogens have been subjected to functional genomic analysis, we still understand little about bacteria-invertebrate interactions despite their ecological prevalence. Advances in our knowledge of this area are often hindered by the difficulty of isolating and working with invertebrate pathogenic bacteria and their hosts. Here we review studies on pathogenicity and symbiosis in an insect pathogenic bacterium Photorhabdus and its entomopathogenic nematode vector and model insect hosts. Whilst switching between these hosts, Photorhabdus changes from a state of symbiosis with its nematode vector to one of pathogenicity towards its new insect host and both the bacteria and the nematode then cooperatively exploit the dying insect. We examine candidate genes involved in symbiosis and pathogenicity, their secretion and expression patterns in culture and in the host, and begin to dissect the extent of their genetic coregulation. We describe the presence of several large genomic islands, putatively involved in pathogenicity or symbiosis, within the otherwise Yersinia-like backbone of the Photorhabdus genome. Finally, we examine the emerging comparative genomics of the Photorhabdus group and begin to describe the interrelationship between anti-invertebrate virulence factors and those used against vertebrates.     

Species distribution models for Peruvian plantcutter improve with consideration of biotic interactions

Biotic interactions have been controversial in distributional ecology, mainly in regards to whether they have effects over broad extents, with the negative view known as the Eltonian noise hypothesis (ENH). In this study, we evaluated the ENH for Phytotoma raimondii, a restricted‐range Peruvian endemic bird species: we developed models based on 1) only abiotic conditions, 2) only host plant distributions, and 3) both abiotic conditions and host plant distributions; models were evaluated with partial receiver operating characteristic test and Akaike information criteria metrics. We rejected the ENH for this case: biotic interactions improved the model. The frequency with which exceptions to the ENH are detected has important implications for distributional ecology and methods for estimating distributions of species.     

Viral proteomics: global evaluation of viruses and their interaction with the host

Viruses constantly adapt to and modulate the host environment during replication and propagation. Both DNA and RNA viruses encode multifunctional proteins that interact with and modify host cell proteins. While viral genomes were the first complete sequences known, the corresponding proteomes are only now elucidated, with some surprising results. Even more daunting is the task to globally monitor the impact of viral infection on the proteome of the host cell and many technical hurdles must still be overcome in order to facilitate robust and reproducible measurements. Further complicating the picture is the dynamic nature of proteins, including post-translational modifications, enzymatic cleavage and activation or destruction by proteolytic events. Nevertheless, several promising studies have been published using high-throughput methods directly measuring protein abundance. Particularly, quantitative or semiquantitative mass spectrometry-based analysis of viral and cellular proteomes are now being used to characterize viruses and their host interaction. In addition, the full set of interactions between viral and host proteins, the interactome, is beginning to emerge, with often unexpected interactions that need to be carefully validated. In this review, we will discuss two major areas of viral proteomics: first, virion proteomics (such as the protein characterization of viral particles) and second, proteoviromics, including the viral protein interactomics and the quantitative analysis of host cell proteome during viral infection.     

Advances in the genomics of ticks and tick-borne pathogens

Ticks and the diseases for which they are vectors engage in complex interactions with their mammalian hosts. These interactions involve the developmental processes of tick and pathogen, and interplay between the defensive responses and counter responses of host, tick and pathogen. Understanding these interactions has long been an intractable problem, but progress is now being made thanks to the flood of genomic information on host, tick and pathogen, and the attendant, novel experimental tools that have been generated. Each advance reveals new levels of complexity, but there are encouraging signs that genomics is leading to novel means of parasite control.     

Manganese and fungal pathogens: Metabolism and potential association with virulence

Nutritional immunity is one of the strategies employed by the host to combat invading pathogens. It consists of actively controlling micronutrient bioavailability in the site of infection to hinder microbial growth. The role of manganese in cell biology and nutritional immunity for bacterial pathogens is well understood, but data regarding fungi are still limited. Fungi have evolved complex regulatory systems to acquire, distribute, and utilize manganese. Therefore, the disruption of manganese homeostasis in pathogenic fungi may lead to severe phenotypes and impact virulence. Because the host presents tools for manganese sequestration, and this condition can reduce the growth of important fungal pathogens such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, it is feasible to suppose that manganese nutritional immunity could play an important role in fungal infections. However, direct evidence is still lacking, and little is known about manganese homeostasis, nutritional immunity, and specific adaptations in individual species of fungal pathogens. In this opinion, we present the current body of knowledge about these subjects, arguing about manganese importance in host–pathogen interactions.     

The role of defensive symbionts in host–parasite coevolution

Understanding the coevolution of hosts and parasites is a long‐standing goal of evolutionary biology. There is a well‐developed theoretical framework to describe the evolution of host–parasite interactions under the assumption of direct, two‐species interactions, which can result in arms race dynamics or sustained genotype fluctuations driven by negative frequency dependence (Red Queen dynamics). However, many hosts rely on symbionts for defence against parasites. Whilst the ubiquity of defensive symbionts and their potential importance for disease control are increasingly recognized, there is still a gap in our understanding of how symbionts mediate or possibly take part in host–parasite coevolution. Herein we address this question by synthesizing information already available from theoretical and empirical studies. First, we briefly introduce current hypotheses on how defensive mutualisms evolved from more parasitic relationships and highlight exciting new experimental evidence showing that this can occur very rapidly. We go on to show that defensive symbionts influence virtually all important determinants of coevolutionary dynamics, namely the variation in host resistance available to selection by parasites, the specificity of host resistance, and the trade‐off structure between host resistance and other components of fitness. In light of these findings, we turn to the limited theory and experiments available for such three‐species interactions to assess the role of defensive symbionts in host–parasite coevolution. Specifically, we discuss under which conditions the defensive symbiont may take over from the host the reciprocal adaptation with parasites and undergo its own selection dynamics, thereby altering or relaxing selection on the hosts' own immune defences. Finally, we address potential effects of defensive symbionts on the evolution of parasite virulence. This is an important problem for which there is no single, clear‐cut prediction. The selection on parasite virulence resulting from the presence of defensive symbionts in their hosts will depend on the underlying mechanism of defence. We identify the evolutionary predictions for different functional categories of symbiont‐conferred resistance and we evaluate the empirical literature for supporting evidence. We end this review with outstanding questions and promising avenues for future research to improve our understanding of symbiont‐mediated coevolution between hosts and parasites.     

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

Bornaviruses are the only animal RNA viruses that establish a persistent infection in their host cell nucleus. Studies of bornaviruses have provided unique information about viral replication strategies and virus–host interactions. Although bornaviruses do not integrate into the host genome during their replication cycle, we and others have recently reported that there are DNA sequences derived from the mRNAs of ancient bornaviruses in the genomes of vertebrates, including humans, and these have been designated endogenous borna-like (EBL) elements. Therefore, bornaviruses have been interacting with their hosts as driving forces in the evolution of host genomes in a previously unexpected way. Studies of EBL elements have provided new models for virology, evolutionary biology and general cell biology. In this review, we summarize the data on EBL elements including what we have newly identified in eukaryotes genomes, and discuss the biological significance of EBL elements, with a focus on EBL nucleoprotein elements in mammalian genomes. Surprisingly, EBL elements were detected in the genomes of invertebrates, suggesting that the host range of bornaviruses may be much wider than previously thought. We also review our new data on non-retroviral integration of Borna disease virus.     

Poxvirus Proteomics and Virus-Host Protein Interactions

Summary: Studies of the functional proteins encoded by the poxvirus genome provide information about the composition of the virus as well as individual virus-virus protein and virus-host protein interactions, which provides insight into viral pathogenesis and drug discovery. Widely used proteomic techniques to identify and characterize specific protein-protein interactions include yeast two-hybrid studies and coimmunoprecipitations. Recently, various mass spectrometry techniques have been employed to identify viral protein components of larger complexes. These methods, combined with structural studies, can provide new information about the putative functions of viral proteins as well as insights into virus-host interaction dynamics. For viral proteins of unknown function, identification of either viral or host binding partners provides clues about their putative function. In this review, we discuss poxvirus proteomics, including the use of proteomic methodologies to identify viral components and virus-host protein interactions. High-throughput global protein expression studies using protein chip technology as well as new methods for validating putative protein-protein interactions are also discussed.     

靶向宿主致病菌sRNA的发现及其靶标确定的实验技术进展

人类时常暴露于充满各种致病菌的环境中,这些致病菌与人体细胞或组织之间存在多种相互作用。在相互作用的过程中,细菌通过调节自身毒性、侵袭性等致病性,以适应宿主环境并生存下来,同样,宿主细胞也会通过调动自身的免疫系统来抵抗致病菌的入侵。然而,大多数研究者主要聚焦于致病菌sRNA (small RNA, sRNA)自身生理功能的研究,致病菌与宿主相互作用的认识仍然处于起步阶段。因此,如何使用高灵敏性、高分辨率的方法研究致病菌与宿主之间的相互作用成为当前研究面临的一大难题。本文综合国内外相关研究,概述了目前研究致病菌与宿主相互作用常用的技术方法及实验流程,提高对其机制原理的理解,为致病菌sRNA-宿主靶标的相关研究提供技术参考。     

Predicting enhancer-promoter interaction from genomic sequence with deep neural networks

Background: In the human genome, distal enhancers are involved in regulating target genes through proximal promoters by forming enhancer-promoter interactions. Although recently developed high-throughput experimental approaches have allowed us to recognize potential enhancer-promoter interactions genome-wide, it is still largely unclear to what extent the sequence-level information encoded in our genome help guide such interactions. Methods: Here we report a new computational method (named “SPEID”) using deep learning models to predict enhancer-promoter interactions based on sequence-based features only, when the locations of putative enhancers and promoters in a particular cell type are given. Results: Our results across six different cell types demonstrate that SPEID is effective in predicting enhancer-promoter interactions as compared to state-of-the-art methods that only use information from a single cell type. As a proof-of-principle, we also applied SPEID to identify somatic non-coding mutations in melanoma samples that may have reduced enhancer-promoter interactions in tumor genomes. Conclusions: This work demonstrates that deep learning models can help reveal that sequence-based features alone are sufficient to reliably predict enhancer-promoter interactions genome-wide.     

A structural overview of mycobacterial adhesins: Key biomarkers for diagnostics and therapeutics

Adherence, colonization, and survival of mycobacteria in host cells require surface adhesins, which are attractive pharmacotherapeutic targets. A large arsenal of pilus and non‐pilus adhesins have been identified in mycobacteria. These adhesins are capable of interacting with host cells, including macrophages and epithelial cells and are essential to microbial pathogenesis. In the last decade, several structures of mycobacterial adhesins responsible for adhesion to either macrophages or extra cellular matrix proteins have been elucidated. In addition, key structural and functional information have emerged for the process of mycobacterial adhesion to epithelial cells, mediated by the Heparin‐binding hemagglutinin (HBHA). In this review, we provide an overview of the structural and functional features of mycobacterial adhesins and discuss their role as important biomarkers for diagnostics and therapeutics. Based on the reported data, it appears clear that adhesins are endowed with a variety of different structures and functions. Most adhesins play important roles in the cell life of mycobacteria and are key virulence factors. However, they have adapted to an extracellular life to exert a role in host‐pathogen interaction. The type of interactions they form with the host and the adhesin regions involved in binding is partly known and is described in this review.     

Cryptosporidium excystation and invasion: getting to the guts of the matter

Cryptosporidium parvum excystation and host cell invasion have been characterized in some detail ultrastructurally. However, until recently, the biochemical and molecular basis of host-parasite interactions and parasite- and host-specific molecules involved in excystation, motility and host cell invasion have been poorly understood. This article describes our understanding of Cryptosporidium excystation and the events leading to host cell invasion, and draws from information available about these processes in other apicomplexans. Many questions remain but, once the specific mechanisms are identified, they could prove to be novel targets for drug delivery.     

Virus mediated trophic interactions between aphids and their natural enemies

Microbial endosymbionts alter the phenotype of their host which may have cascading effects at both population and community levels. However, we currently lack information on whether the effects of viruses on both host phenotypic traits and host population demography can modify interactions with upper trophic levels. To fill this gap, we investigated whether a prevalent densovirus infecting the aphid Myzus persicae (i.e. MpDNV) can modify trophic interactions between host aphids and their natural enemies (i.e. predators and parasitoids) by influencing aphid phenotypic traits (i.e. body mass and defensive behaviours), population demography (i.e. density and age-structure) and susceptibility towards both predation and parasitism. We found that the virus decreased aphid body mass but did not influence their behavioural defences. At the population level, the virus had a minor effect on aphid adult mortality whereas it strongly reduced the density of nymphs and influenced the stage structure of aphid populations. In addition, the virus enhanced the susceptibility of aphids to parasitism regardless of the parasitoid species. Predation rate on adult aphids was not influenced by the virus but ladybeetle predators strongly decreased the number of aphid nymphs, especially for uninfected ones compared to infected ones. As a result, the virus decreased predator effect on aphid populations. By reducing both aphid quality and availability, increasing their susceptibility to parasitism, and modulating predator effect on aphid populations, we highlighted that viral endosymbionts can be prevalent drivers of their host ecology as they modify their phenotypes and interspecific interactions. These virus-mediated ecological effects may have consequences on enemies foraging strategies as well as trophic webs dynamics and structure.