Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

<div><p>Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.</p></div

ZIKV infection induces an antiviral state within human DCs.

<p>moDCs were infected with ZIKV PR-2015, P6-1966, MR-1947, or Dak-1984 at MOI of 1 (n = 6–8 donors). Cells were collected at indicated hours post-infection and antiviral gene expression was determined by qRT-PCR. Gene expression was normalized to <i>GAPDH</i> transcript levels in each respective sample and represented as the averaged log₂ normalized fold increase above donor and time-point matched uninfected cells. The averaged log₁₀ normalized levels of infectious virus (FFU/mL) at each time point is depicted beneath the gene expression heat map. <b>(A)</b> RLR gene expression. <b>(B)</b> Antiviral effector gene expression. <b>(C)</b> moDCs were left untreated (“Mock”), treated with RIG-I agonist (10ng/1e5 cells), or infected with ZIKV PR-2015 (MOIs of 1 and 10) or MR-1947 (MOI 1). After 18hrs of agonist treatment or at 48hpi with ZIKV, whole-cell lysates were collected for western blot analysis of host antiviral effector protein expression. Western blots are shown for a single donor and are representative of data obtained from two donors. See also <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006164#ppat.1006164.s005" target="_blank">S5 Fig</a>.</p

Differential infection of human DCs by evolutionarily distinct ZIKV strains.

<p>moDCs were infected with PR-2015, P6-1966, MR-1947, or Dak-1984 at MOI of 1 and assessed for viral replication at the indicated hours post-infection. <b>(A)</b> Infectious virus release into the supernatant was determined by FFA. Shown as the mean +/- SEM from 6–9 donors. <b>(B)</b> Infectious virus release for 6 of the individual donors summarized in panel A. <b>(C)</b> Percent infected cells assessed by ZIKV E protein staining and flow cytometry. Shown as the mean +/- SEM from 6–9 donors. <b>(D)</b> Percent infected cells in 6 of the individual donors summarized in panel C. <b>(E)</b> Cell viability of infected moDCs assessed by Ghost Red 780 (Tonbo) viability staining and flow cytometry. Shown as the mean +/- SEM from 6–9 donors. Statistical significance (p< 0.05) was determined using a two-way ANOVA with comparisons made to mock-infected cells. See also <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006164#ppat.1006164.s007" target="_blank">S1 Table</a>.</p

ZIKV infection minimally activates human DCs.

<p><b>(A)</b> moDCs were left uninfected (“Mock”) or infected with PR-2015, P6-1966, MR-1947, or Dak-1984 at MOI of 1 (n = 6–8 donors). Cells were collected at 48hpi and labeled for ZIKV E protein and indicated DC activation markers. Cells were categorized as being viral E protein- or viral E protein+ and activation marker surface expression quantitated by flow cytometry. Values are represented as median fluorescence intensity (MFI) for each individual donor with uninfected and ZIKV infected samples from the same donor connected with a line. Statistical significance (p< 0.05) was determined using a Friedman test with comparisons made to donor-paired, uninfected cells. <b>(B)</b> moDCs infected with PR-2015 at MOI of 1 were stratified into “low” (n = 3 donors) and “high” (n = 5 donors) infection on the basis of viral E protein staining. MFIs are shown as the mean +/- SD. See also <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006164#ppat.1006164.s003" target="_blank">S3 Fig</a>.</p