Response to Dangl: Complex harmonies of the host–pathogen interaction

In the accompanying Research Focus article that summarises our recent research article [1], Jeffery Dangl likens the interplay of the intracellular pathogen Salmonella enterica serovar Typhimurium with the host resistance protein Nramp1 to the response of a congregation to the teachings of a preacher. In principle, this is a fair interpretation of what we believe to be occurring on the molecular level between host and pathogen within the limited scope of our experiments. However, as with most biological systems, we believe that this analogy might be too simplistic. As Dangl points out, Nramp1 ‘might have a multitude of messages that it sends to different vacuolar inhabitants’. This cannot exclude the fact that the effects of Nramp1 on any single pathogen are pleiotropic and that we focused solely on one aspect of Nramp1 function in our studies, that is, divalent cation limitation. Therefore, we suggest that the interplay between innate host defences and pathogens is far more complex than simple call-and-response. Instead, we propose that it is more like a musical round, where one instrument makes the initial statement of the tune followed by the response of a second instrument, building over successive entrances to a complex orchestral whole. As a case in point, we wish to draw the reader's attention to the complex influences of both Nramp1 and S. enterica Typhimurium on the generation of toxic oxygen and nitrogen intermediates by the host during infection.     

Inhibition of a malaria host–pathogen interaction by a computationally designed inhibitor

Malaria is a substantial global health burden with 229 million cases in 2019 and 450,000 deaths annually. Plasmodium vivax is the most widespread malaria-causing parasite putting 2.5 billion people at risk of infection. P. vivax has a dormant liver stage and therefore can exist for long periods undetected. Its blood-stage can cause severe reactions and hospitalization. Few treatment and detection options are available for this pathogen. A unique characteristic of P. vivax is that it depends on the Duffy antigen/receptor for chemokines (DARC) on the surface of host red blood cells for invasion. P. vivax employs the Duffy binding protein (DBP) to bind to DARC. We first de novo designed a three helical bundle scaffolding database which was screened via protease digestions for stability. Protease-resistant scaffolds highlighted thresholds for stability, which we utilized for selecting DARC mimetics that we subsequentially designed through grafting and redesign of these scaffolds. The optimized design small helical protein disrupts the DBP:DARC interaction. The inhibitor blocks the receptor binding site on DBP and thus forms a strong foundation for a therapeutic that will inhibit reticulocyte infection and prevent the pathogenesis of P. vivax malaria.     

The plant pathogen Rhodococcus fascians. History,disease symptomatology,host range,pathogenesis and plant–pathogen interaction

Since 1927, outbreaks of the leafy gall disease caused by Rhodococcus fascians on annual and perennial herbaceous plants have put the ornamental plant industry at risk. More recently, Pistachio Bushy top syndrome (PBTS), a serious disease emerging in the Western United States, has been declared as a natural disaster by the U.S. Department of Agriculture. Recent developments indicate that the taxonomic position of R. fascians should be re-evaluated and circumscribed from other members of the genus. Due to the broad host range of this bacterium, economically important crops are in a vulnerable position especially with new members within the genus becoming able to interact synergistically with R. fascians to cause symptom development. The virulence strategies employed by R. fascians and the involvement of cytokinins (CKs) in its pathogenicity have been the subject of much controversy in the last years. Additionally, the detection of virulent strains of R. fascians from symptomatic tissues has been problematic for many researchers. This review focuses on plant–pathogen interaction in context with more recent findings on the association of CKs in virulence of R. fascians. Current knowledge on the worldwide distribution of the pathogen, a historical recap of its discovery and the economic impact of the disease caused by R. fascians are also described here.     

Comparative mapping of host–pathogen protein–protein interactions

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Effects of temperature on the host–pathogen interaction in Ascochyta blight (Ascochyta lentis) of lentil

The effects of temperature regimes on the radial growth rate of different isolates of Ascochyta lentis and pathogen virulence and host susceptibility were studied in the laboratory and growth chamber using different pathogen isolates, and lentil genotypes with varying levels of resistance to Ascochyta blight. The growth rate of most isolates increased as temperature increased up to 20°C and declined thereafter. In experiment 1, the highest disease severities were observed on cvs. Laird and Eston and the lowest on ILL5588. Mean disease severities were similar from 10 to 20°C but substantially lower at 25°C for all genotypes except ILL5588. In experiment 2, no significant differences were observed between the two mating types, or in their interactions with genotypes and temperatures. The interactions of genotypes with temperature and with isolates indicated that the relative susceptibility of lentil genotypes depended on temperature and on the isolates of A. lentis. These findings indicated that when temperature changes during epidemic development in the field, different isolates could predominate in the pathogen population at different times.     

Out of the ESCPE room: Emerging roles of endosomal SNX-BARs in receptor transport and host–pathogen interaction

Several functions of the human cell, such as sensing nutrients, cell movement and interaction with the surrounding environment, depend on a myriad of transmembrane proteins and their associated proteins and lipids (collectively termed “cargoes”). To successfully perform their tasks, cargo must be sorted and delivered to the right place, at the right time, and in the right amount. To achieve this, eukaryotic cells have evolved a highly organized sorting platform, the endosomal network. Here, a variety of specialized multiprotein complexes sort cargo into itineraries leading to either their degradation or their recycling to various organelles for further rounds of reuse. A key sorting complex is the Endosomal SNX-BAR Sorting Complex for Promoting Exit (ESCPE-1) that promotes the recycling of an array of cargos to the plasma membrane and/or the trans-Golgi network. ESCPE-1 recognizes a hydrophobic-based sorting motif in numerous cargoes and orchestrates their packaging into tubular carriers that pinch off from the endosome and travel to the target organelle. A wide range of pathogens mimic this sorting motif to hijack ESCPE-1 transport to promote their invasion and survival within infected cells. In other instances, ESCPE-1 exerts restrictive functions against pathogens by limiting their replication and infection. In this review, we discuss ESCPE-1 assembly and functions, with a particular focus on recent advances in the understanding of its role in membrane trafficking, cellular homeostasis and host–pathogen interaction.     

Uncoupling of the dynamics of host–pathogen interaction uncovers new mechanisms of viral interferon antagonism at the single-cell level

Antiviral defence in mammals is mediated through type-I interferons (IFNs). Viruses antagonise this process through expression of IFN antagonist proteins (IAPs). Understanding and modelling of viral escape mechanisms and the dynamics of IAP action has the potential to facilitate the development of specific and safe drugs. Here, we describe the dynamics of interference by selected viral IAPs, NS1 from Influenza A virus and NS3/4A from Hepatitis C virus. We used Tet-inducible IAP gene expression to uncouple this process from virus-driven dynamics. Stochastic activation of the IFN-β gene required the use of single-cell live imaging to define the efficacy of the inhibitors during the virus-induced signalling processes. We found significant correlation between the onset of IAP expression and halted IFN-β expression in cells where IFN-β induction had already occurred. These data indicate that IAPs not only prevent antiviral signalling prior to IFN-β induction, but can also stop the antiviral response even after it has been activated. We found reduced NF-κB activation to be the underlying mechanism by which activated IFN expression can be blocked. This work demonstrates a new mechanism by which viruses can antagonise the IFN response.     

Evolutionary implications of host–pathogen specificity: the fitness consequences of host life history traits

Pathogens and parasites can be strong agents of selection, and often exhibit some degree of genetic specificity for individual host strains. Here we show that this host–pathogen specificity can affect the evolution of host life history traits. All else equal, evolution should select for genes that increase individuals' reproduction rates or lifespans (and thus total reproduction per individual). Using a simple host–pathogen model, we show that when the genetic specificity of pathogen infection is low, host strains with higher reproduction rates or longer lifespans drive slower-reproducing or shorter-lived host strains to extinction, as one would expect. However, when pathogens exhibit specificity for host strains with different life history traits, the evolutionary advantages of these traits can be greatly diminished by pathogen-mediated selection. Given sufficient host–pathogen specificity, pathogen-mediated selection can maintain polymorphism in host traits that are correlated with pathogen resistance traits, despite large intrinsic fitness differences among host strains. These results have two important implications. First, selection on host life history traits will be weaker than expected, whenever host fitness is significantly affected by genotype-specific pathogen attack. Second, where polymorphism in host traits is maintained by pathogen-mediated selection, preserving the genetic diversity of host species may require preserving their pathogens as well. This revised version was published online in November 2006 with corrections to the Cover Date.     

The helminth holobiont: a multidimensional host–parasite–microbiota interaction

Gastrointestinal helminths have developed multiple mechanisms by which they manipulate the host microbiome to make a favorable environment for their long-term survival. While the impact of helminth infections on vertebrate host immunity and its gut microbiota is relatively well studied, little is known about the structure and functioning of microbial populations supported by metazoan parasites. Here we argue that an integrated understanding of the helminth-associated microbiome and its role in the host disease pathogenesis may facilitate the discovery of specific microbial and/or genetic patterns critical for parasite biology and subsequently pave the way for the development of alternative control strategies against parasites and parasitic disease.     

MicroRNAs as mediators of insect host–pathogen interactions and immunity

Insects are the most successful group of animals on earth, owing this partly to their very effective immune responses to microbial invasion. These responses mainly include cellular and humoral responses as well as RNA interference (RNAi). Small non-coding RNAs (snRNAs) produced through RNAi are important molecules in the regulation of gene expression in almost all living organisms; contributing to important processes such as development, differentiation, immunity as well as host–microorganism interactions. The main snRNAs produced by the RNAi response include short interfering RNAs, microRNAs and piwi-interacting RNAs. In addition to the host snRNAs, some microorganisms encode snRNAs that affect the dynamics of host–pathogen interactions. In this review, we will discuss the latest developments in regards to the role of microRNA in insect host–pathogen interactions and provide some insights into this rapidly developing area of research.     

Comparative analysis of Leishmania exoproteomes: Implication for host–pathogen interactions

Leishmaniasis is a vector-borne disease caused by the protozoa Leishmania. We have analyzed and compared the sequences of three experimental exoproteomes of Leishmania promastigotes from different species to determine their specific features and to identify new candidate proteins involved in interactions of Leishmania with the host. The exoproteomes differ from the proteomes by a decrease in the average molecular weight per protein, in disordered amino acid residues and in basic proteins. The exoproteome of the visceral species is significantly enriched in sites predicted to be phosphorylated as well as in features frequently associated with molecular interactions (intrinsic disorder, number of disordered binding regions per protein, interaction and/or trafficking motifs) compared to the other species. The visceral species might thus have a larger interaction repertoire with the host than the other species. Less than 10% of the exoproteomes contain heparin-binding and RGD sequences, and ~ 30% the host targeting signal RXLXE/D/Q. These latter proteins might thus be exported inside the host cell during the intracellular stage of the infection. Furthermore we have identified nine protein families conserved in the three exoproteomes with specific combinations of Pfam domains and selected eleven proteins containing at least three interaction and/or trafficking motifs including two splicing factors, phosphomannomutase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, the paraflagellar rod protein-1D and a putative helicase. Their role in host–Leishmania interactions warrants further investigation but the putative ATP-dependent DEAD/H RNA helicase, which contains numerous interaction motifs, a host targeting signal and two disordered regions, is a very promising candidate.     

Characterization of the Sulfolobus host–SSV2 virus interaction

The Sulfolobus spindle virus, SSV2, encodes a tyrosine integrase which furthers provirus formation in host chromosomes. Consistently with the prediction made during sequence analysis, integration was found to occur in the downstream half of the tRNA^Gly (CCC) gene. In this paper we report the findings of a comparative study of SSV2 physiology in the natural host, Sulfolobus islandicus REY15/4, versus the foreign host, Sulfolobus solfataricus, and provide evidence of differently regulated SSV2 life cycles in the two hosts. In fact, whereas a significant induction of SSV2 replication takes place during the growth of the natural host REY15/4, the cellular content of SSV2 DNA remains fairly low throughout the incubation of the foreign host. The accumulation of episomal DNA in the former case cannot be traced to decreased packaging activity because of a simultaneous increase in the virus titre in the medium. In addition, the interaction between SSV2 and its natural host is characterized by the concurrence of host growth inhibition and the induction of viral DNA replication. When this virus–host interaction was investigated using S. islandicus REY15A, a strain which is closely related to the natural host, it was found that the SSV2 replication process was induced in the same way as in the natural host REY15/4.     

Persistent host–parasitoid interaction caused by host maturation variability

The heterogeneity of parasitism risk among host individuals is a key factor for stabilizing or sustaining host–parasitoid interactions. Host maturation variability, or the variation in the maturation times among host individuals, is the simplest source of such heterogeneity, but it has often been neglected in previous theoretical studies. We developed a configuration individual-based model (cIBM) of host–parasitoid interaction to investigate to what degree of host maturation variability promotes the persistence of host–parasitoid interactions. We ran simulations with various degrees of host maturation variability for different lengths of unsusceptible period. The result showed that low host maturation variability could sustain host–parasitoid dynamics when the host-unsusceptible period was short. Conversely, high levels of variability could sustain host–parasitoid dynamics when the host-unsusceptible period was about half of the total larval period. This suggests that the balance between variability and unsusceptible period is important for the persistence of host–parasitoid interaction. We conclude that maturation variability is a factor that can contribute to the sustainment of host–parasitoid interactions.     

The Iron age of host–microbe interactions

Microbes exert a major impact on human health and disease by either promoting or disrupting homeostasis, in the latter instance leading to the development of infectious diseases. Such disparate outcomes are driven by the ever-evolving genetic diversity of microbes and the countervailing host responses that minimize their pathogenic impact. Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes. While genetically distinct, these host defense strategies are functionally integrated, via mechanisms that remain incompletely defined. Here, we explore the general principles via which host adaptive responses regulating iron (Fe) metabolism impact on resistance and disease tolerance to infection.     

The roles of ABA in plant–pathogen interactions

Defence against abiotic and biotic stresses is crucial for the fitness and survival of plants under adverse or suboptimal growth conditions. The phytohormone abscisic acid (ABA) is not only important for mediating abiotic stress responses, but also plays a multifaceted and pivotal role in plant immunity. This review presents examples demonstrating the importance of crosstalk between ABA and the key biotic stress phytohormone salicylic acid in determining the outcome of plant–pathogen interactions. We then provide an overview of how ABA influences plant defence responses against various phytopathogens with particular emphasis on the Arabidopsis–Pseudomonas syringae model pathosystem. Lastly, we discuss future directions for studies of ABA in plant immunity with emphasis on, its role in the crosstalk between biotic and abiotic stress responses, the importance of distinguishing direct and indirect effects of ABA, as well as the prospect of utilizing the recently elucidated core ABA signaling network to gain further insights into the roles of ABA in plant immunity.