Host–pathogen interactions: a proteomic view

Host–pathogen interactions reflect the balance of host defenses and pathogen virulence mechanisms. Advances in proteomic technologies now afford opportunities to compare protein content between complex biologic systems ranging from cells to animals and clinical samples. Thus, it is now possible to characterize host–pathogen interactions from a global proteomic view. Most reports to date focus on cataloging protein content of pathogens and identifying virulence-associated proteins or proteomic alterations in host response. A more in-depth understanding of host–pathogen interactions has the potential to improve our mechanistic understanding of pathogenicity and virulence, thereby defining novel therapeutic and vaccine targets. In addition, proteomic characterization of the host response can provide pathogen-specific host biomarkers for rapid pathogen detection and characterization, as well as for early and specific detection of infectious diseases. A review of host–pathogen interactions focusing on proteomic analyses of both pathogen and host will be presented. Relevant genomic studies and host model systems will be also be discussed.     

Host-pathogen interactions during apoptosis

Host pathogen interaction results in a variety of responses, which include phagocytosis of the pathogen, release of cytokines, secretion of toxins, as well as production of reactive oxygen species (ROS). Recent studies have shown that many pathogens exert control on the processes that regulate apoptosis in the host. The induction of apoptosis upon infection results from a complex interaction of parasite proteins with cellular host proteins. Abrogation of host cell apoptosis is often beneficial for the pathogen and results in a successful host invasion. However, in some cases, it has been shown that induction of apoptosis in the infected cells significantly imparts protection to the host from the pathogen. There is a strong correlation between apoptosis and the host protein translation machinery: the pathogen makes all possible efforts to modify this process so as to inhibit cell suicide and ensure that it can survive and, in some cases, establish latent infection. This review discusses the significance of various pathways/steps during virus-mediated modulation of host cell apoptosis.     

Oxidative stress response: a proteomic view

The oxidative stress response is characterized by various effects on a range of biologic molecules. When examined at the protein level, both expression levels and protein modifications are altered by oxidative stress. While these effects have been studied in the past by classic biochemical methods, the recent onset of proteomics methods has allowed the oxidative stress response to be studied on a much wider scale. The input of proteomics in the study of oxidative stress response and in the evidence of an oxidative stress component in biologic phenomena is reviewed in this paper.     

Oxidative stress response: a proteomic view

The oxidative stress response is characterized by various effects on a range of biologic molecules. When examined at the protein level, both expression levels and protein modifications are altered by oxidative stress. While these effects have been studied in the past by classic biochemical methods, the recent onset of proteomics methods has allowed the oxidative stress response to be studied on a much wider scale. The input of proteomics in the study of oxidative stress response and in the evidence of an oxidative stress component in biologic phenomena is reviewed in this paper.     

Alpha-synuclein and Parkinson's disease: a proteomic view

In this review, we report how proteomic methodologies have been used to investigate cellular and animal models of Parkinson's disease (PD), with a special focus on alpha-synuclein. PD is a complex, multifactorial neurodegenerative disease affecting approximately 2% of the population over 65 years of age, pathologically characterized by alpha-synuclein intraneuronal inclusions. Etiopathogenetic mechanisms of PD are not fully understood, although a number of factors contributing to the selective degeneration of substantia nigra neurons have been identified. Therefore, cellular and animal models of the disease have been developed to investigate single factors contributing to disease pathogenesis; for example, alpha-synuclein aggregation and altered dopamine homeostasis. Proteomic studies on cellular and animal models have not only confirmed existing theories on PD pathogenesis (mitochondrial impairment, oxidative stress, failure of the ubiquitine-proteasome system), but also allowed the discovery of new important common features of presymptomatic (or premotor) stages of PD, such as dysregulation of cytoskeletal proteins that could be involved at the origin of the disorder.     

Host-pathogen interactions revealed by human genome-wide surveys

Genome-wide association studies (GWAS) have now convincingly shown that the diverse outcomes (such as the resolution of infection, clinical deterioration to severe disease, or progression from acute infection to persistent infection) that occur following microbial infection can be at least partly explained by human genetic variation. Unbiased whole-genome approaches have revealed unprecedentedly robust associations between genetic markers and susceptibility to disease, providing clear insights into our understanding of infectious disease biology by revealing the crucial host-pathogen interaction sites. Further work characterizing both the host causative variations and pathogenic microbial strains with distinct host interactions and disease outcomes is now required to provide potential new intervention strategies.     

Host-pathogen interactions: cheating the host by making new connections

Dynamic signaling networks are required to perform complex cellular processes. Structural and functional data now indicate the intriguing possibility that extracellular bacterial pathogens use catalytic scaffolds to assemble unique supramolecular signaling networks that effectively subvert key cellular processes in the host.     

Host-pathogen interactions in a varying environment: temperature,behavioural fever and fitness

We demonstrate how variable temperatures, mediated by host thermoregulation and behavioural fever, critically affect the interaction between a host (the desert locust, Schistocerca gregaria) and a pathogen (the fungus Metarhizium anisopliae var. acridum). By means of behavioural thermoregulation, infected locusts can raise their body temperatures to fever levels. The adaptive value of this behaviour was examined using three thermal regimes wherein maximum body temperatures achievable were: (i) below, or (ii) at normally preferred temperatures, or were (iii) unrestricted, allowing heightened fever temperatures. All infected locusts ultimately succumbed to disease, with median survival times of 8, 15 and 21 days post-infection, respectively. Crucially, only those locusts able to fever produced viable offspring. This represents, to our knowledge, the first demonstration of the adaptive value of behavioural fever following infection with a naturally occurring pathogen. By contrast, although normal host thermoregulation moderately reduced pathogen reproduction (by 35%), there was no additional negative effect of fever, resulting in an asymmetry in the fitness consequences of fever for the host and the pathogen. The dependency of the host-pathogen interaction upon external abiotic conditions has implications for how virulence and resistance are treated both theoretically and in the management of pests and diseases.     

Host-pathogen interactions between the skin and Staphylococcus aureus

Staphylococcus aureus is responsible for the vast majority of bacterial skin infections in humans. The propensity for S. aureus to infect skin involves a balance between cutaneous immune defense mechanisms and virulence factors of the pathogen. The tissue architecture of the skin is different from other epithelia especially since it possesses a corneal layer, which is an important barrier that protects against the pathogenic microorganisms in the environment. The skin surface, epidermis, and dermis all contribute to host defense against S. aureus. Conversely, S. aureus utilizes various mechanisms to evade these host defenses to promote colonization and infection of the skin. This review will focus on host-pathogen interactions at the skin interface during the pathogenesis of S. aureus colonization and infection.     

Evolution of the secretoglobins: a genomic and proteomic view

Mouse salivary androgen-binding protein (ABP) is a member of the newly erected secretoglobin family, no member of which has yet been assigned an indisputable function. We have suggested a role for ABP in mate selection behaviour and sexual isolation. Although this has been a particularly attractive hypothesis given the evidence for strong positive selection on its alpha subunit gene, Abpa , we have held out the possibility that there might be an as-yet-undiscovered primary function for ABP. This is particularly important in light of its membership in the secretoglobin family, and we are pursuing the broader issue of shared functions of the secretoglobins with genomic and bioinformatic studies. Here we present as complete a comparison as possible of the secretoglobins in the genomes of three species of mammals: mouse, rat and human, and we compare the protein sequences and their potential evolutionary relationships. We suggest that the secretoglobins can be divided into at least five families. In rodent and human genomes, these gene families are found in two main clusters that are syntenic between rat and mouse. Humans have only the three families that are found within the uteroglobin/clara cluster, because no ABP-containing secretoglobin cluster has yet been identified.  © 2005 The Linnean Society of London, Biological Journal of the Linnean Society , 2005, 84 , 493–501.     

Mitochondria in the pathogenesis of diabetes: a proteomic view

Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes.     

Hirsutella thompsoniU a fungal pathogen of mites. II. Host-pathogen interactions

The moniliaceous fungus, Hirsutella thompsoniU grown on potato-dextrose agar (PDA) or on sterile wheat bran, was highly pathogenic to the carmine spider mite, Tetranychus cinnabarinus, and, grown on PDA, to the oriental spider mite, Eutetranychus orientalis. The fungus penetrated the mites' integument mainly through the legs and formed hyphal bodies in chains in the haemolymph. Hyphae, on which the spores were produced, began to emerge through the genital and anal apertures and then all over the body. Various mycophagous mites, a predaceous species and the tick Argas persicus were immune. H. thompsonii grew well on cadavers of diverse insects and mites. The fungus killed most mites and quickest, usually by the 2nd day, at 25^o, 27^o and 30 ^oC; least at 13^o and 35 ^oC. It sporulated best on mites at 24^o, 27^o and 30 ^oC (full sporulation at 27 ^oC took place within 12 h after death); it was good, but slower, at 13^o and 35 ^oC. The fungus germinated, penetrated mites and sporulated there very poorly below 100% r.h. When the daily number of hours at 100% r.h. was reduced from 24 to 18 or 6 h, fungus-associated mortality dropped greatly. In the field, use of the fungus for mite control would be suitable particularly in tropical and humid subtropical areas, and its success in Israel would not be assured. In glasshouses, H. thompsonii could induce epizootics in Israel and elsewhere only if humidities were raised to saturation and the daytime temperature kept below 37 ^oC.     

A proteomic view of mycobacteria

Tuberculosis, the disease caused by Mycobacterium tuberculosis, remains a relevant public health issue. This is due mostly to the coepidemiology with HIV/AIDS, the appearance of multidrug-resistant strains globally, and failure of BCG (bacillus Calmette-Guerin) vaccination to confer complete protection. This bacterium was one of the first to have its genome sequenced, yet over a decade after the release of the genomic information, the characterization of its phylogenetic tree and of different strain variants inside this species revealed that much is still needed to be done for a full understanding of the M. tuberculosis genome and proteome. Current methods using LC-MS/MS and hybrid high-resolution mass spectrometers can identify 2400-2800 proteins of the 4000 predicted genes in M. tuberculosis. In this article, we review relevant details of this bacterium's pathology and immunology, describing articles where proteomics helped the community to tackle some of the organism biology, from understanding strain diversity, cellular structure composition, immunogenicity, and host-pathogen interactions. Finally, we will discuss the challenges yet to be fulfilled in order to better characterize M. tuberculosis by proteomics.     

Unraveling the factors and mechanism involved in persistence: Host-pathogen interactions in Helicobacter pylori

Helicobacter pylori and humans have one of the most complex relationships in nature. How a bacterium manages to live in one of the harshest and hostile environments is a topic of unraveling mysteries. H. pylori is a prevalent species and it colonizes the human gut of more than 50% of the world population. It infects the epithelial region of antrum and persists there for a long period. Over the time of evolution, H. pylori has developed complex strategies to extend the degree of inflammation in gastric mucosa. H. pylori needs specific adaptations for initial colonization into the host environment like helical shape, flagellar movement, chemotaxis, and the production of urease enzyme that neutralizes acidic environment of the stomach. There are several factors from the bacterium as well as from the host that participate in these complex interactions. On the other hand, to establish the persistent infection, H. pylori escapes the immune system by mimicking the host antigens. This pathogen has the ability to dodge the immune system and then persist there in the form of host cell, which leads to immune tolerance. H. pylori has an ability to manipulate its own pathogen-associated molecular patterns, which leads to an inhibition in the binding with specific pattern recognition receptors of the host to avoid immune cell detection. Also, it manipulates the host metabolic homeostasis in the gastric epithelium. Besides, it has several genes, which may get involved in the acquisition of nutrition from the host to survive longer in the host. Due to the persistence of H. pylori, it causes chronic inflammation and raises the chances of gastric cancer. This review highlights the important elements, which are certainly responsible for the persistence of H. pylori in the human host.     

Host-pathogen interactions in natural populations of Linum marginale and Melampsora lini

Summary The epidemiology of rust caused by the fungus Melampsora lini and the effects of infection by this pathogen on its host, the herbaceous perennial Linum marginale, were determined in the field and in garden experiments. There was considerable natural variability in disease levels over the four years (1986–1989) of the study. In two years (1986, 1989) major rust epidemics occurred. In the field, the main effect of disease was to reduce survivorship during the winter following infection. Plants which were heavily infected during the 1986 or 1989 growing seasons had reduced survivorship relative to more lightly infected plants. Melampsora lini infections did not appear to affect survivorship in either 1987 or 1988. Flowering was correlated with environmental factors and the number of stems a plant possessed. A severe drought in 1987 completely inhibited flowering. In the other three years the number of flowers produced by a plant was strongly positively correlated with the number of stems it possessed. Disease levels had no consistent effect on flowering. Controlled garden experiments were also used to examine the response of seedlings and adult plants to infection. These showed that both the timing and severity of disease appears to determine the effect of M. lini infections on L. marginale. Early, severe infection reduced growing season and overwintering survivorship as well as capsule production. However, plants in the field were most often infected only after flowering had begun, and the predominant effect of infection was a reduction in overwintering survivorship. The high variability in disease levels from year to year and the deferred nature of the effect of the rust on its host have significant implications for the design of experiments aimed at assessing the role of diseases in plant communities.