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.     

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: 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 coevolution in human tuberculosis

Tuberculosis (TB) is a disease of antiquity. Yet TB today still causes more adult deaths than any other single infectious disease. Recent studies show that contrary to the common view postulating an animal origin for TB, Mycobacterium tuberculosis complex (MTBC), the causative agent of TB, emerged as a human pathogen in Africa and colonized the world accompanying the Out-of-Africa migrations of modern humans. More recently, evolutionarily 'modern' lineages of MTBC expanded as a consequence of the global human population increase, and spread throughout the world following waves of exploration, trade and conquest. While epidemiological data suggest that the different phylogenetic lineages of MTBC might have adapted to different human populations, overall, the phylogenetically 'modern' MTBC lineages are more successful in terms of their geographical spread compared with the 'ancient' lineages. Interestingly, the global success of 'modern' MTBC correlates with a hypo-inflammatory phenotype in macrophages, possibly reflecting higher virulence, and a shorter latency in humans. Finally, various human genetic variants have been associated with different MTBC lineages, suggesting an interaction between human genetic diversity and MTBC variation. In summary, the biology and the epidemiology of human TB have been shaped by the long-standing association between MTBC and its human host.     

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.     

Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast

Haploinsufficiency is defined as a dominant phenotype in diploid organisms that are heterozygous for a loss-of-function allele. Despite its relevance to human disease, neither the extent of haploinsufficiency nor its precise molecular mechanisms are well understood. We used the complete set of Saccharomyces cerevisiae heterozygous deletion strains to survey the genome for haploinsufficiency via fitness profiling in rich (YPD) and minimal media to identify all genes that confer a haploinsufficient growth defect. This assay revealed that approximately 3% of all approximately 5900 genes tested are haploinsufficient for growth in YPD. This class of genes is functionally enriched for metabolic processes carried out by molecular complexes such as the ribosome. Much of the haploinsufficiency in YPD is alleviated by slowing the growth rate of each strain in minimal media, suggesting that certain gene products are rate limiting for growth only in YPD. Overall, our results suggest that the primary mechanism of haploinsufficiency in yeast is due to insufficient protein production. We discuss the relevance of our findings in yeast to human haploinsufficiency disorders.     

Common gene expression strategies revealed by genome-wide analysis in yeast

Background  

Gene expression is a two-step synthesis process that ends with the necessary amount of each protein required to perform its function. Since the protein is the final product, the main focus of gene regulation should be centered on it. However, because mRNA is an intermediate step and the amounts of both mRNA and protein are controlled by their synthesis and degradation rates, the desired amount of protein can be achieved following different strategies.     

An IL-7 splicing-defect lymphopenia mouse model revealed by genome-wide mutagenesis

Homeostasis of the hematopoietic system is tightly regulated by an array of cytokines that control proliferation, differentiation and apoptosis of various cell lineages. To identify genes that are essential for hematopoietic homeostasis, we screened C57BL/6 mice that had been genome-wide mutagenized by N-ethyl-N-nitrosourea (ENU) to produce altered blood cell composition. We identified a mutant mouse line with a drastic reduction in the number of T and B cell lineages in lymphatic tissues and peripheral blood, as well as severe atrophy of the thymus and lymph nodes. Genotyping with a genome-wide single nucleotide polymorphism (SNP) marker set mapped the mutant phenotype to chromosome 3A and subsequent direct DNA sequencing revealed a G-to-A point mutation in the splicing donor site of the third exon of the candidate gene for IL-7, a lymphocyte survival cytokine. Such mutation resulted in skipping of exon 3 and production of an internally truncated IL-7 (ΔE3-IL7). Furthermore, using recombinant proteins produced in a baculoviral system, we demonstrated that ΔE3-IL7 had no detectable anti-apoptotic activity even at a dose that was 30 times more than that required for a wild-type protein to manifest a full activity in a naïve T cell survival assay. Our data suggest that this mutant mouse line?provides an alternative animal model for the study of severe combined immunodeficiency (SCID) syndrome in humans.     

Actin-fragmin interactions as revealed by chemical cross-linking

A one to one complex of actin and fragmin (a capping protein from Physarum polycephalum plasmodia) was cross-linked with 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide. The cross-linking reaction generated two cross-linked products with slightly different molecular weights (88 000 and 90 000) as major species. They were cross-linked products of one actin and one fragmin. The cross-linking site of fragmin in the actin sequence was determined by peptide mappings [Sutoh, K. (1982) Biochemistry 21, 3654-3661] after partial chemical cleavages of cross-linked products with hydroxylamine. The results indicated that the N-terminal segment of actin spanning residues 1-12 participated in cross-linking with fragmin. The cross-linker used in this study covalently bridges lysine side chains and side chains of acidic residues when they are in direct contact. Therefore, it seems that acidic residues in the N-terminal segment of actin (Asp-1, Glu-2, Asp-3, Glu-4, and Asp-11), at least some of them, are in the binding site of fragmin. It has already been shown that the same acidic segment of actin is in the binding site of myosin or depactin (an actin-depolymerizing protein isolated from starfish oocytes). We suggest that the unusual amino acid sequence of the N-terminal segment of actin makes its N-terminal region a favorable anchoring site for various types of actin-binding proteins.     

Chromosome conformation capture uncovers potential genome-wide interactions between human conserved non-coding sequences

Comparative analyses of various mammalian genomes have identified numerous conserved non-coding (CNC) DNA elements that display striking conservation among species, suggesting that they have maintained specific functions throughout evolution. CNC function remains poorly understood, although recent studies have identified a role in gene regulation. We hypothesized that the identification of genomic loci that interact physically with CNCs would provide information on their functions. We have used circular chromosome conformation capture (4C) to characterize interactions of 10 CNCs from human chromosome 21 in K562 cells. The data provide evidence that CNCs are capable of interacting with loci that are enriched for CNCs. The number of trans interactions varies among CNCs; some show interactions with many loci, while others interact with few. Some of the tested CNCs are capable of driving the expression of a reporter gene in the mouse embryo, and associate with the oligodendrocyte genes OLIG1 and OLIG2. Our results underscore the power of chromosome conformation capture for the identification of targets of functional DNA elements and raise the possibility that CNCs exert their functions by physical association with defined genomic regions enriched in CNCs. These CNC-CNC interactions may in part explain their stringent conservation as a group of regulatory sequences.     

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.     

Prediction of locally stable RNA secondary structures for genome-wide surveys

MOTIVATION: Recently novel classes of functional RNAs, most prominently the miRNAs have been discovered, strongly suggesting that further types of functional RNAs are still hidden in the recently completed genomic DNA sequences. Only few techniques are known, however, to survey genomes for such RNA genes. When sufficiently similar sequences are not available for comparative approaches the only known remedy is to search directly for structural features. RESULTS: We present here efficient algorithms for computing locally stable RNA structures at genome-wide scales. Both the minimum energy structure and the complete matrix of base pairing probabilities can be computed in theta(N x L2) time and theta(N + L2) memory in terms of the length N of the genome and the size L of the largest secondary structure motifs of interest. In practice, the 100 Mb of the complete genome of Caenorhabditis elegans can be folded within about half a day on a modern PC with a search depth of L = 100. This is sufficient example for a survey for miRNAs. AVAILABILITY: The software described in this contribution will be available for download at http://www.tbi.univie.ac.at/~ivo/RNA/ as part of the Vienna RNA Package.     

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.     

Genetic architecture of photosynthesis energy partitioning as revealed by a genome-wide association approach

Photosynthesis Research - The photosynthesis process is determined by the intensity level and spectral quality of the light; therefore, leaves need to adapt to a changing environment. The incident...     

Associations between HIV and human pathways revealed by protein-protein interactions and correlated gene expression profiles

Background

AIDS is one of the most devastating diseases in human history. Decades of studies have revealed host factors required for HIV infection, indicating that HIV exploits host processes for its own purposes. HIV infection leads to AIDS as well as various comorbidities. The associations between HIV and human pathways and diseases may reveal non-obvious relationships between HIV and non-HIV-defining diseases.

Principal Findings

Human biological pathways were evaluated and statistically compared against the presence of HIV host factor related genes. All of the obtained scores comparing HIV targeted genes and biological pathways were ranked. Different rank results based on overlapping genes, recovered virus-host interactions, co-expressed genes, and common interactions in human protein-protein interaction networks were obtained. Correlations between rankings suggested that these measures yielded diverse rankings. Rank combination of these ranks led to a final ranking of HIV-associated pathways, which revealed that HIV is associated with immune cell-related pathways and several cancer-related pathways. The proposed method is also applicable to the evaluation of associations between other pathogens and human pathways and diseases.

Conclusions

Our results suggest that HIV infection shares common molecular mechanisms with certain signaling pathways and cancers. Interference in apoptosis pathways and the long-term suppression of immune system functions by HIV infection might contribute to tumorigenesis. Relationships between HIV infection and human pathways of disease may aid in the identification of common drug targets for viral infections and other diseases.