Surfactant protein D modulates HIV infection of both T-cells and dendritic cells

Surfactant Protein D (SP-D) is an oligomerized C-type lectin molecule with immunomodulatory properties and involvement in lung surfactant homeostasis in the respiratory tract. SP-D binds to the enveloped viruses, influenza A virus and respiratory syncytial virus and inhibits their replication in vitro and in vivo. SP-D has been shown to bind to HIV via the HIV envelope protein gp120 and inhibit infectivity in vitro. Here we show that SP-D binds to different strains of HIV (BaL and IIIB) and the binding occurs at both pH 7.4 and 5.0 resembling physiological relevant pH values found in the body and the female urogenital tract, respectively. The binding of SP-D to HIV particles and gp120 was inhibited by the presence of several hexoses with mannose found to be the strongest inhibitor. Competition studies showed that soluble CD4 and CVN did not interfere with the interaction between SP-D and gp120. However, soluble recombinant DC-SIGN was shown to inhibit the binding between SP-D and gp120. SP-D agglutinated HIV and gp120 in a calcium dependent manner. SP-D inhibited the infectivity of HIV strains at both pH values of 7.4 and 5.0 in a concentration dependent manner. The inhibition of the infectivity was abolished by the presence of mannose. SP-D enhanced the binding of HIV to immature monocyte derived dendritic cells (iMDDCs) and was also found to enhance HIV capture and transfer to the T-cell like line PM1. These results suggest that SP-D can bind to and inhibit direct infection of T-cells by HIV but also enhance the transfer of infectious HIV particles from DCs to T-cells in vivo

Learning efficacy of explicit visuomotor sequences in children with attention-deficit/hyperactivity disorder and Asperger syndrome

Developmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and Asperger syndrome (AS) are often associated with learning disabilities. This study investigated the explicit learning of visuomotor sequences in 17 ADHD children (mean age 12.1), 21 AS children (mean age 12.7), and 15 typically developing children (mean age: 12.3). The participants were required to explore a hidden sequence of button presses by trial and error and elaborate the learned sequence (2 × 10 task: Hikosaka et al. 1996). The results indicated that although ADHD and AS children had a tendency of repeating the same errors and took longer to complete a sequence, both showed a degree and pattern of improvement in accuracy and speed similar to that of typically developing children. These results suggest that the explicit learning of visuomotor sequence in ADHD and AS patients is largely unimpaired

Molecular Analysis of Serum and Bronchoalveolar Lavage in a Mouse Model of Influenza Reveals Markers of Disease Severity That Can Be Clinically Useful in Humans

Background: Management of influenza, a major contributor to the worldwide disease burden, is complicated by lack of reliable methods for early identification of susceptible individuals. Identification of molecular markers that can augment existing diagnostic tools for prediction of severity can be expected to greatly improve disease management capabilities. Methodology/Principal Findings: We have analyzed cytokines, proteome flux and protein adducts in bronchoalveolar lavage (BAL) and sera from mice infected with influenza A virus (PR8 strain) using a previously established non-lethal model of influenza infection. Through detailed cytokine and protein adduct measurements of murine BAL, we first established the temporal profile of innate and adaptive responses as well as macrophage and neutrophil activities in response to influenza infection. A similar analysis was also performed with sera from a longitudinal cohort of influenza patients. We then used an iTRAQ-based, comparative serum proteome analysis to catalog the proteome flux in the murine BAL during the stages correlating with “peak viremia,” “inflammatory damage,” as well as the “recovery phase.” In addition to activation of acute phase responses, a distinct class of lung proteins including surfactant proteins was found to be depleted from the BAL coincident with their “appearance” in the serum, presumably due to leakage of the protein following loss of the integrity of the lung/epithelial barrier. Serum levels of at least two of these proteins were elevated in influenza patients during the febrile phase of infection compared to healthy controls or to the same patients at convalescence. Conclusions/Significance: The findings from this study provide a molecular description of disease progression in a mouse model of influenza and demonstrate its potential for translation into a novel class of markers for measurement of acute lung injury and improved case management.Singapore. National Research FoundationSingapore-MIT Alliance for Research and Technology (ID-IRG research program

Susceptibility to ozone-induced airway inflammation is associated with decreased levels of surfactant protein D

BACKGROUND: Ozone (O(3)), a common air pollutant, induces exacerbation of asthma and chronic obstructive pulmonary disease. Pulmonary surfactant protein (SP)-D modulates immune and inflammatory responses in the lung. We have shown previously that SP-D plays a protective role in a mouse model of allergic airway inflammation. Here we studied the role and regulation of SP-D in O(3)-induced inflammatory changes in the lung. METHODS: To evaluate the effects of O(3 )exposure in mouse strains with genetically different expression levels of SP-D we exposed Balb/c, C57BL/6 and SP-D knockout mice to O(3 )or air. BAL cellular and cytokine content and SP-D levels were evaluated and compared between the different strains. The kinetics of SP-D production and inflammatory parameters were studied at 0, 2, 6, 12, 24, 48, and 72 hrs after O(3 )exposure. The effect of IL-6, an O(3)-inducible cytokine, on the expression of SP-D was investigated in vitro using a primary alveolar type II cell culture. RESULTS: Ozone-exposed Balb/c mice demonstrated significantly enhanced acute inflammatory changes including recruitment of inflammatory cells and release of KC and IL-12p70 when compared with age- and sex-matched C57BL/6 mice. On the other hand, C57BL/6 mice had significantly higher levels of SP-D and released more IL-10 and IL-6. Increase in SP-D production coincided with the resolution of inflammatory changes. Mice deficient in SP-D had significantly higher numbers of inflammatory cells when compared to controls supporting the notion that SP-D has an anti-inflammatory function in our model of O(3 )exposure. IL-6, which was highly up-regulated in O(3 )exposed mice, was capable of inducing the expression of SP-D in vitro in a dose dependent manner. CONCLUSION: Our data suggest that IL-6 contributes to the up-regulation of SP-D after acute O(3 )exposure and elevation of SP-D in the lung is associated with the resolution of inflammation. Absence or low levels of SP-D predispose to enhanced inflammatory changes following acute oxidative stress

A Novel Pathogenic Mechanism of Highly Pathogenic Avian Influenza H5N1 Viruses Involves Hemagglutinin Mediated Resistance to Serum Innate Inhibitors

In this study, the effect of innate serum inhibitors on influenza virus infection was addressed. Seasonal influenza A(H1N1) and A(H3N2), 2009 pandemic A(H1N1) (H1N1pdm) and highly pathogenic avian influenza (HPAI) A(H5N1) viruses were tested with guinea pig sera negative for antibodies against all of these viruses as evaluated by hemagglutination-inhibition and microneutralization assays. In the presence of serum inhibitors, the infection by each virus was inhibited differently as measured by the amount of viral nucleoprotein produced in Madin-Darby canine kidney cells. The serum inhibitors inhibited seasonal influenza A(H3N2) virus the most, while the effect was less in seasonal influenza A(H1N1) and H1N1pdm viruses. The suppression by serum inhibitors could be reduced by heat inactivation or treatment with receptor destroying enzyme. In contrast, all H5N1 strains tested were resistant to serum inhibitors. To determine which structure (hemagglutinin (HA) and/or neuraminidase (NA)) on the virus particles that provided the resistance, reverse genetics (rg) was applied to construct chimeric recombinant viruses from A/Puerto Rico/8/1934(H1N1) (PR8) plasmid vectors. rgPR8-H5 HA and rgPR8-H5 HANA were resistant to serum inhibitors while rgPR8-H5 NA and PR8 A(H1N1) parental viruses were sensitive, suggesting that HA of HPAI H5N1 viruses bestowed viral resistance to serum inhibition. These results suggested that the ability to resist serum inhibition might enable the viremic H5N1 viruses to disseminate to distal end organs. The present study also analyzed for correlation between susceptibility to serum inhibitors and number of glycosylation sites present on the globular heads of HA and NA. H3N2 viruses, the subtype with highest susceptibility to serum inhibitors, harbored the highest number of glycosylation sites on the HA globular head. However, this positive correlation cannot be drawn for the other influenza subtypes

Physical and emotional health outcomes after 12 months of public-sector antiretroviral treatment in the Free State Province of South Africa: a longitudinal study using structural equation modelling

<p>Abstract</p> <p>Background</p> <p>African and Asian cohort studies have demonstrated the clinical efficacy of antiretroviral treatment (ART) in resource-limited settings. However, reports of the long-term changes in the physical and emotional quality of life (QoL) of patients on ART in these settings are still scarce. In this study, we assessed the physical and emotional QoL after six and 12 months of ART of a sample of 268 patients enrolled in South Africa's public-sector ART programme. The study also tested the impact of the adverse effects of medication on patients' physical and emotional QoL.</p> <p>Methods</p> <p>A stratified random sample of 268 patients undergoing ART was interviewed at baseline (< 6 months ART) and follow-up (< 12 months ART). A model of the relationships between the duration of ART, the adverse effects of medication, and physical and emotional QoL (measured using EUROQOL-5D) was tested using structural equation modelling.</p> <p>Results</p> <p>The improved physical and emotional QoL shown at baseline was sustained over the 12-month study period, because treatment duration was not significantly associated with changes in the patients' QoL. Physical QoL significantly and positively influenced the patients' emotional QoL (subjective well-being [SWB]) (β = 0.33, <it>P </it>< 0.01). Longitudinal data showed that patients reported significantly fewer adverse effects at follow-up than at baseline (β = -0.38, <it>P </it>< 0.001) and that these adverse effects negatively influenced physical (β = -0.27, <it>P </it>< 0.01) and emotional QoL (β = -0.15, <it>P </it>< 0.05).</p> <p>Conclusion</p> <p>This study provides evidence that the South African public-sector ART programme is effective in delivering sustained improvement in patient well-being. However, the results should encourage clinicians and lay health workers to be vigilant regarding the adverse effects of treatment, because they can seriously affect physical and emotional QoL.</p

Inhibition, Reinforcement Sensitivity and Temporal Information Processing in ADHD and ADHD+ODD: Evidence of a Separate Entity?

This study compared children with ADHD-only, ADHD+ODD and normal controls (age 8–12) on three key neurocognitive functions: response inhibition, reinforcement sensitivity, and temporal information processing. The goal was twofold: (a) to investigate neurocognitive impairments in children with ADHD-only and children with ADHD+ODD, and (b) to test whether ADHD+ODD is a more severe from of ADHD in terms of neurocognitive performance. In Experiment 1, inhibition abilities were measured using the Stop Task. In Experiment 2, reinforcement sensitivity and temporal information processing abilities were measured using a Timing Task with both a reward and penalty condition. Compared to controls, children with ADHD-only demonstrated impaired inhibitory control, showed more time underestimations, and showed performance deterioration in the face of reward and penalty. Children with ADHD+ODD performed in-between children with ADHD-only and controls in terms of inhibitory controls and the tendency to underestimate time, but were more impaired than controls and children with ADHD-only in terms of timing variability. In the face of reward and penalty children with ADHD+ODD improved their performance compared to a neutral condition, in contrast to children with ADHD-only. In the face of reward, the performance improvement in the ADHD+ODD group was disproportionally larger than that of controls. Taken together the findings suggest that, in terms of neurocognitive functioning, comorbid ADHD+ODD is a substantial different entity than ADHD-only