Host cellular signaling induced by influenza virus

A wide range of host cellular signal transduction pathways can be stimulated by influenza virus infection. Some of these signal transduction pathways induce the host cell’s innate immune response against influenza virus, while others are essential for efficient influenza virus replication. This review examines the cellular signaling induced by influenza virus infection in host cells, including host pattern recognition receptor (PRR)-related signaling, protein kinase C (PKC), Raf/MEK/ERK and phosphatidylinositol- 3-kinase (PI3K)/Akt signaling, and the corresponding effects on the host cell and/or virus, such as recognition of virus by the host cell, viral absorption and entry, viral ribonucleoprotein (vRNP) export, translation control of cellular and viral proteins, and virus-induced cell apoptosis. Research into influenza virus-induced cell signaling promotes a clearer understanding of influenza virus-host interactions and assists in the identification of novel antiviral targets and antiviral strategies.     

The role of mathematical models of host-pathogen interactions for livestock health and production - a review

Compared with the application of mathematical models to study human diseases, models that describe animal responses to pathogen challenges are relatively rare. The aim of this review is to explain and show the role of mathematical host-pathogen interaction models in providing underpinning knowledge for improving animal health and sustaining livestock production. Existing host-pathogen interaction models can be assigned to one of three categories: (i) models of the infection and immune system dynamics, (ii) models that describe the impact of pathogen challenge on health, survival and production and (iii) models that consider the co-evolution of host and pathogen. State-of-the-art approaches are presented and discussed for models belonging to the first two categories only, as they concentrate on the host-pathogen dynamics within individuals. Models of the third category fall more into the class of epidemiological models, which deserve a review by themselves. An extensive review of published models reveals a rich spectrum of methodologies and approaches adopted in different modelling studies, and a strong discrepancy between models concerning diseases in animals and models aimed at tackling diseases in humans (most of which belong to the first category), with the latter being generally more sophisticated. The importance of accounting for the impact of infection not only on health but also on production poses a considerable challenge to the study of host-pathogen interactions in livestock. This has led to relatively simplistic representations of host-pathogen interaction in existing models for livestock diseases. Although these have proven appropriate for investigating hypotheses concerning the relationships between health and production traits, they do not provide predictions of an animal's response to pathogen challenge of sufficient accuracy that would be required for the design of appropriate disease control strategies. A synthesis between the modelling methodologies adopted in categories 1 and 2 would therefore be desirable. The progress achieved in mathematical modelling to study immunological processes relevant to human diseases, together with the current advances in the generation and analysis of biological data related to animal diseases, offers a great opportunity to develop a new generation of host-pathogen interaction models that take on a fundamental role in the study and control of disease in livestock.     

Growth responses and fitness costs after induction of pathogen resistance depend on environmental conditions

Fitness costs of resistance are among the most widely discussed explanations for the evolution of induced resistance, but studies on induced resistance to pathogens are scarce and contradictory. In the present study the influence of nitrogen supply, length of the growing period and competition on the seed production of Arabidopsis in response to treatment with the chemical resistance elicitor BION^® was investigated. BION^® treatment elicited resistance to the bacterial pathogen Pseudomonas syringae, and biochemical changes after BION^® treatment were similar to those observed after bacterial infection. Induced plants grew more slowly during the first week after resistance induction, for which they then compensated by exhibiting faster growth than controls. Whether or not induced plants produced less seeds than controls depended on growing conditions. Costs, no costs and even higher seed production by induced plants were observed in experiments differently combining abiotic conditions. A higher seed production by induced plants arose particularly when the vegetation period was short, most probably a consequence of senescence-related processes that had been activated by resistance elicitation. Induced plants, however, produced less seeds when competing with controls and experiencing a full growing period. Studies controlling only some of the critical environmental factors can easily lead to apparently contradictory results, which in fact represent different outcomes of a complex interplay of factors.     

Differential susceptibility epidemic models

We formulate compartmental differential susceptibility (DS) susceptible-infective-removed (SIR) models by dividing the susceptible population into multiple subgroups according to the susceptibility of individuals in each group. We analyze the impact of disease-induced mortality in the situations where the number of contacts per individual is either constant or proportional to the total population. We derive an explicit formula for the reproductive number of infection for each model by investigating the local stability of the infection-free equilibrium. We further prove that the infection-free equilibrium of each model is globally asymptotically stable by qualitative analysis of the dynamics of the model system and by utilizing an appropriately chosen Liapunov function. We show that if the reproductive number is greater than one, then there exists a unique endemic equilibrium for all of the DS models studied in this paper. We prove that the endemic equilibrium is locally asymptotically stable for the models with no disease-induced mortality and the models with contact numbers proportional to the total population. We also provide sufficient conditions for the stability of the endemic equilibrium for other situations. We briefly discuss applications of the DS models to optimal vaccine strategies and the connections between the DS models and predator-prey models with multiple prey populations or host-parasitic interaction models with multiple hosts are also given.This research was partially supported by the Department of Energy under contracts W-7405-ENG-36 and the Applied Mathematical Sciences Program KC-07-01-01.     

An analysis of genetic variation across the MBL2 locus in Dutch Caucasians indicates that 3′ haplotypes could modify circulating levels of mannose-binding lectin

Mannose-binding protein (MBL) is a critical component of innate immunity and provides first-line protection against pathogens. Both circulating MBL serum levels and functional activity have been correlated with common genetic variants in the MBL2 gene. Associations between MBL deficiency and severe infections have been reported in immuno-incompetent patients and for autoimmune disorders; however, measured MBL serum levels do not fully correlate with the ‘secretor haplotypes’. Previously, the MBL2 locus was resequenced and determined that a recombination hotspot divides MBL2 into two haplotype blocks. It was sought to investigate whether additional variants, in either block structure could associate with MBL serum levels. Therefore, 31 common variants were analysed across the locus in 212 DNA samples of healthy Caucasian individuals with known MBL serum concentrations. The additional 5′ variants were in strong linkage to the elements of the ‘secretor haplotypes’; functional alleles B, C and D also lie on restricted haplotypes. Four variants in the 3′ block (Ex4-1483T>C, Ex4-1067G>A, Ex4-901G>A and Ex4-710G>A) are components of a distinct haplotype block. The results of this study suggest that additional 5′ variants as well as markers of distinct 3′ haplotype blocks in MBL2 may contribute to circulating protein levels, but further studies are required to confirm these observations. Last, there could be a selective advantage for diversification of the 3′ region of the gene.Electronic Supplementary Material Supplementary material is available for this article at     

Comparison of QTL controlling seedling vigour under different temperature conditions using recombinant inbred lines in rice (Oryza sativa)

BACKGROUND AND AIMS: Seedling vigour is one of the major determinants for stable stand establishment in rice (Oryza sativa), especially in a direct seeding cropping system. The objectives of this study were to identify superior alleles with consistent effects on seedling vigour across different temperature conditions and to investigate genotype x environmental temperature interactions for seedling vigour QTL. METHODS: A set of 282 F13 recombinant inbred lines (RILs) derived from a rice cross were assessed for four seedling vigour traits at three temperatures (25 degrees C, 20 degrees C and 15 degrees C). Using a linkage map with 198 marker loci, the main-effect QTL for the traits were mapped by composite interval mapping. KEY RESULTS: A total of 34 QTL for the four seedling vigour traits were identified. Of these QTL, the majority (82%) were clustered within five genomic regions, designated as QTL qSV-3-1, qSV-3-2, qSV-5, qSV-8-1 and qSV-8-2. All of these five QTL had small individual effects on the traits, explaining 3.1-15.8 % of the phenotypic variation with a mean of 7.3 %. QTL qSV-3-1, qSV-3-2 and qSV-8-1 showed almost consistent effects on the traits across all three temperatures while qSV-5 and qSV-8-2 had effects mainly at the 'normal' temperatures of 20 degrees C and 25 degrees C. Among the five QTL identified, all and four showed additive effects on shoot length and germination rate, respectively. The contributions of these five QTL to shoot length and germination rate were also much larger than those to the other two traits. CONCLUSIONS: A few of genomic regions (or QTL) were identified as showing effects on seedling vigour. For these QTL, significant genotype x environmental temperature interactions were found and these interactions appeared to be QTL-specific. Among the four seedling vigour traits measured, shoot length and germination rate could be used as relatively good indicators to evaluate the level of seedling vigour in rice.     

Assessing treatment effect heterogeneity in clinical trials with blocked binary outcomes

This paper addresses treatment effect heterogeneity (also referred to, more compactly, as 'treatment heterogeneity') in the context of a controlled clinical trial with binary endpoints. Treatment heterogeneity, variation in the true (causal) individual treatment effects, is explored using the concept of the potential outcome. This framework supposes the existance of latent responses for each subject corresponding to each possible treatment. In the context of a binary endpoint, treatment heterogeniety may be represented by the parameter, pi2, the probability that an individual would have a failure on the experimental treatment, if received, and would have a success on control, if received. Previous research derived bounds for pi2 based on matched pairs data. The present research extends this method to the blocked data context. Estimates (and their variances) and confidence intervals for the bounds are derived. We apply the new method to data from a renal disease clinical trial. In this example, bounds based on the blocked data are narrower than the corresponding bounds based only on the marginal success proportions. Some remaining challenges (including the possibility of further reducing bound widths) are discussed.     

Design and analysis of drug combination experiments

In this paper we present and discuss a novel, simple and easy to implement parametric modeling approach to assess synergy. An extended three parameter log-logistic model is used to analyse the data and calculate confidence intervals of the interaction indices. In addition the model corrects for the bias due to plate-location effects. The analysis is performed with PROC NLMIXED and SAS-code is provided. The approach is illustrated using data coming from an oncology study in which the inhibition effect of a combination of two compounds is studied using 96-well plates and a fixed-ratio design.     

The variable C-terminus of 14-3-3 proteins mediates isoform-specific interaction with sucrose-phosphate synthase in the yeast two-hybrid system

Sucrose-6-phosphate synthase (SPS) is a target for 14-3-3 protein binding in plants. Because several isoforms of the 14-3-3 protein are expressed in plants, I investigated which isoforms have the ability to bind SPS. Two 14-3-3 isoforms (T14-3d and a novel isoform designated T14-3 g) were found to interact with SPS from tobacco (Nicotiana tabacum L.) in a two-hybrid screen. To further address the question of isoform specificity of 14-3-3s, four additional isoforms were tested for their ability to interact with SPS in the yeast two-hybrid system. The results clearly revealed large differences in affinity between individual 14-3-3 isoforms toward SPS. Deletion analysis suggested that these differences were mediated by the variable C-terminus of 14-3-3s. Site-directed mutagenesis of candidate 14-3-3 binding sites on SPS demonstrated that interaction could be independent of a phosphorylated serine residue within conserved binding motifs in the yeast system. These findings suggest that the large number of 14-3-3 isoforms present in plants reflects functional specificity.     

Structural insights into the EB1-APC interaction

EB1 proteins bind to microtubule ends where they act in concert with other components, including the adenomatous polyposis coli (APC) tumor suppressor, to regulate the microtubule filament system. We find that EB1 is a stable dimer with a parallel coiled coil and show that dimerization is essential for the formation of its C-terminal domain (EB1-C). The crystal structure of EB1-C reveals a highly conserved surface patch with a deep hydrophobic cavity at its center. EB1-C binds two copies of an APC-derived C-terminal peptide (C-APCp1) with equal 5 microM affinity. The conserved APC Ile2805-Pro2806 sequence motif serves as an anchor for the interaction of C-APCp1 with the hydrophobic cavity of EB1-C. Phosphorylation of the conserved Cdc2 site Ser2789-Lys2792 in C-APCp1 reduces binding four-fold, indicating that the interaction APC-EB1 is post-translationally regulated in cells. Our findings provide a basis for understanding the dynamic crosstalk of EB1 proteins with their molecular targets in eukaryotic organisms.