Sequence Variants of Toll Like Receptor 4 and Late-Onset Alzheimer's Disease

Background

Toll like receptor 4 (TLR4) has been related to inflammation and beta-amyloid deposition in Alzheimer''s disease (AD) brain. No study has explored the association between haplotype-tagging single nucleotide polymorphisms (htSNPs) of TLR4 and AD risk previously and ApoE e4 status alone showed low sensitivity in identifying late-onset AD (LOAD) patients.

Methods

A total of 269 LOAD patients were recruited from three hospitals in northern Taiwan (2007–2010). Controls (n = 449) were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) TLR4 htSNPs were selected to assess the association between TLR4 polymorphisms and the risk of LOAD in the Chinese ethnic population.

Results

Homozygosity of TLR4 rs1927907 was significantly associated with an increased risk of LOAD [TT vs. CC: adjusted odds ratio (AOR) = 2.45, 95% confidence interval (CI) = 1.30–4.64]. After stratification, the association increased further in ApoE e4 non-carriers (AOR = 3.07) and in hypertensive patients (AOR = 3.60). Haplotype GACGG was associated with a decreased risk of LOAD (1 vs. 0 copies: AOR = 0.59, 95% CI = 0.36–0.96; 2 vs. 0 copies: AOR = 0.31, 95% CI = 0.14–0.67) in ApoE e4 non-carriers. ApoE e4 status significantly modified this association (p _interaction = 0.01). These associations remained significant after correction for multiple tests.

Conclusions

Sequence variants of TLR4 were associated with an increased risk of LOAD, especially in ApoE e4 non-carriers and in hypertensive patients. The combination of TLR4 rs1927907 and ApoE e4 significantly increased the screening sensitivity in identifying LOAD patients from 0.4 to 0.7.     

Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model

In terms of its highly pathogenic nature, there remains a significant need to further define the immune pathology of SARS-coronavirus (SARS-CoV) infection, as well as identify correlates of immunity to help develop vaccines for severe coronaviral infections. Here we use a SARS-CoV infection-reinfection ferret model and a functional genomics approach to gain insight into SARS immunopathogenesis and to identify correlates of immune protection during SARS-CoV-challenge in ferrets previously infected with SARS-CoV or immunized with a SARS virus vaccine. We identified gene expression signatures in the lungs of ferrets associated with primary immune responses to SARS-CoV infection and in ferrets that received an identical second inoculum. Acute SARS-CoV infection prompted coordinated innate immune responses that were dominated by antiviral IFN response gene (IRG) expression. Reinfected ferrets, however, lacked the integrated expression of IRGs that was prevalent during acute infection. The expression of specific IRGs was also absent upon challenge in ferrets immunized with an inactivated, Al(OH)₃-adjuvanted whole virus SARS vaccine candidate that protected them against SARS-CoV infection in the lungs. Lack of IFN-mediated immune enhancement in infected ferrets that were previously inoculated with, or vaccinated against, SARS-CoV revealed 9 IRG correlates of protective immunity. This data provides insight into the molecular pathogenesis of SARS-CoV and SARS-like-CoV infections and is an important resource for the development of CoV antiviral therapeutics and vaccines.     

Hemopoietic cell expression of the chemokine decoy receptor D6 is dynamic and regulated by GATA1

D6 scavenges inflammatory chemokines and is essential for the regulation of inflammatory and immune responses. Mechanisms explaining the cellular basis for D6 function have been based on D6 expression by lymphatic endothelial cells. In this study, we demonstrate that functional D6 is also expressed by murine and human hemopoietic cells and that this expression can be regulated by pro- and anti-inflammatory agents. D6 expression was highest in B cells and dendritic cells (DCs). In myeloid cells, LPS down-regulated expression, while TGF-beta up-regulated expression. Activation of T cells with anti-CD3 and soluble CD28 up-regulated mRNA expression 20-fold, while maturation of human macrophage and megakaryocyte precursors also up-regulated D6 expression. Competition assays demonstrated that chemokine uptake was D6 dependent in human leukocytes, whereas mouse D6-null cells failed to uptake and clear inflammatory chemokines. Furthermore, we present evidence indicating that D6 expression is GATA1 dependent, thus explaining D6 expression in myeloid progenitor cells, mast cells, megakaryocytes, and DCs. We propose a model for D6 function in which leukocytes, within inflamed sites, activate D6 expression and thus trigger resolution of inflammatory responses. Our data on D6 expression by circulating DCs and B cells also suggest alternative roles for D6, perhaps in the coordination of innate and adaptive immune responses. These data therefore alter our models of in vivo D6 function and suggest possible discrete, and novel, roles for D6 on lymphatic endothelial cells and leukocytes.     

Sex identification of owls (family Strigidae) using oligonucleotide microarrays

Molecular sexing of the diversified avian family Strigidae is difficult. Sex identification using the intron length difference between W and Z chromosomal CHD1 genes, as visualized by agarose gel electrophoreses, often produces ambiguous results. Here we describe a simple method for sexing a variety of Strigidae species using oligonucleotide microarrays, on which several sex-specific probes operated complementarily or in concert. The sex of 8 owl species was identified clearly on the microarrays through sequence recognition. This sequence-directed method can be easily applied to a wider range of Strigidae species.     

MORPHOLOGICAL AND GENETIC VARIATION IN THE POPULATIONS OF SARGASSUM HEMIPHYLLUM (PHAEOPHYCEAE) IN THE NORTHWESTERN PACIFIC1

Difficulty in species identification of Sargassum (Sargassaceae, Fucales) is partly attributed to the high polymorphism among its individuals and populations. This study aimed at assessing morphological and genetic variations in two varieties, var. hemiphyllum J. Agardh and var. chinense J. Agardh, of Sargassum hemiphyllum (Turner) C. Agardh, a widely distributed species in the northwestern Pacific. We investigated 26 measurable, five numerical, and 33 categorical morphological parameters associated with different branching levels of specimens from each of six localities within its distribution range using cluster analysis (CA) and principal coordinate analysis (PCoA). Leaf size of the primary and secondary branching levels and the vesicle size of the secondary branches of the specimens examined were determined to be the most important morphological parameters that were significantly different among populations. Change in leaf and vesicle length of individuals among the six populations followed a latitudinal gradient, with smaller leaves and vesicles associated with northern populations and larger ones in the southern populations. The possible influence of the gradual change in sea surface temperatures (SSTs) along this gradient in the northwestern Pacific on leaf and vesicle morphologies of this species was suggested. PCR‐RFLP analysis of the RUBISCO spacer in the chloroplast genome revealed two distinct and highly homogenous clades, a China clade and a Japan‐Korea clade, which corresponded to var. chinense and var. hemiphyllum, respectively. The formation of refugia along the “Paleo‐coast” in the East China Sea during glacial periods is suggested to have led to the vicariance of ancestral populations of S. hemiphyllum and thus to have promoted genetic differentiation. The massive freshwater outflow of the Yellow and Yangtze rivers may continue to act as a barrier, prolonging the allopatric distribution of the two varieties.     

The evolution of group-level pathogenic traits

A group-selection model for the evolutionary origin of phase-variation in E. coli is proposed. Populations of commensal strains of E. coli populating mammalian hosts modulate its immune defenses through population-level control of the expression of fimbriae. At any time only a proportion of the population expresses these cell-surface adhesins. Collectively they elicit a host-based nutrient release if the fimbriae expression is low. Too high levels of fimbriation would provoke an inflammatory response and thus intolerable conditions for the cells. The optimal level of fimbriation is a group property and its evolution is difficult to explain by naive individual selection scenarios. This article presents a computational model to simulate the evolution of fimbriae. The two main conclusions of this contribution are: (i) the evolution of this group property requires the population to be partitioned into weakly interacting sub-populations. (ii) Given certain scenarios evolution consistently under-performs, in the sense that it does not find the optimal level of fimbriation.     

H5-type influenza virus hemagglutinin is functionally recognized by the natural killer-activating receptor NKp44

Antiviral immune defenses involve natural killer (NK) cells. We previously showed that the NK-activating receptor NKp44 is involved in the functional recognition of H1-type influenza virus strains by NK cells. In the present study, we investigated the interaction of NKp44 and the hemagglutinin of a primary influenza virus H5N1 isolate. Here we show that recombinant NKp44 recognizes H5-expressing cells and specifically interacts with soluble H5 hemagglutinin. H5-pseudotyped lentiviral particles bind to NK cells expressing NKp44. Following interaction with target cells expressing H5, pseudotyped lentiviral particles, or membrane-associated H5, NK cells show NKp44-mediated induced activity. These findings indicate that NKp44-H5 interactions induce functional NK activation.