Protection against Staphylococcus aureus colonization and infection by B-and T-cell-mediated mechanisms

© 2018 Zhang et al. Staphylococcus aureus is a major cause of morbidity and mortality worldwide. S. aureus colonizes 20 to 80% of humans at any one time and causes a variety of illnesses. Strains that are resistant to common antibiotics further complicate management. S. aureus vaccine development has been unsuccessful so far, largely due to the incomplete understanding of the mechanisms of protection against this pathogen. Here, we studied the role of different aspects of adaptive immunity induced by an S. aureus vaccine in protection against S. aureus bacteremia, dermonecrosis, skin abscess, and gastrointestinal (GI) colonization. We show that, depending on the challenge model, the contributions of vaccine-induced S. aureus-specific antibody and Th1 and Th17 responses to protection are different: antibodies play a major role in reducing mortality during S. aureus bacteremia, whereas Th1 or Th17 responses are essential for prevention of S. aureus skin abscesses and the clearance of bacteria from the GI tract. Both antibody-and T-cell-mediated mechanisms contribute to prevention of S. aureus dermonecrosis. Engagement of all three immune pathways results in the most robust protection under each pathological condition. Therefore, our results suggest that eliciting multipronged humoral and cellular responses to S. aureus antigens may be critical to achieve effective and comprehensive immune defense against this pathogen. IMPORTANCE S. aureus is a leading cause of healthcare-and community-associated bacterial infections. S. aureus causes various illnesses, including bacteremia, meningitis, endocarditis, pneumonia, osteomyelitis, sepsis, and skin and soft tissue infections. S. aureus colonizes between 20 and 80% of humans; carriers are at increased risk for infection and transmission to others. The spread of multidrug-resistant strains limits antibiotic treatment options. Vaccine development against S. aureus has been unsuccessful to date, likely due to an inadequate understanding about the mechanisms of immune defense against this pathogen. The significance of our work is in illustrating the necessity of generating multipronged B-cell, Th1-, and Th17-mediated responses to S. aureus antigens in conferring enhanced and broad protection against S. aureus invasive infection, skin and soft tissue infection, and mucosal colonization. Our work thus, provides important insights for future vaccine development against this pathogen

Dipole radio-frequency power from laser plasmas with no dipole moment

The radio-frequency power radiated from laser-target plasmas in a vacuum can be orders of magnitude greater than expected from such sources that have a negligible electric dipole moment. A model combining the Tidman-Stamper circuit model of a laser-target plasma with the theory of radiation from currents immersed in plasmas, however, predicts scaling of electric-dipole power radiated from laser plasmas in agreement with experiments.Comment: 3 pages, 2 figures, as published in Applied Physics Letter

Reactions of a Be-10 beam on proton and deuteron targets

The extraction of detailed nuclear structure information from transfer reactions requires reliable, well-normalized data as well as optical potentials and a theoretical framework demonstrated to work well in the relevant mass and beam energy ranges. It is rare that the theoretical ingredients can be tested well for exotic nuclei owing to the paucity of data. The halo nucleus Be-11 has been examined through the 10Be(d,p) reaction in inverse kinematics at equivalent deuteron energies of 12,15,18, and 21.4 MeV. Elastic scattering of Be-10 on protons was used to select optical potentials for the analysis of the transfer data. Additionally, data from the elastic and inelastic scattering of Be-10 on deuterons was used to fit optical potentials at the four measured energies. Transfers to the two bound states and the first resonance in Be-11 were analyzed using the Finite Range ADiabatic Wave Approximation (FR-ADWA). Consistent values of the spectroscopic factor of both the ground and first excited states were extracted from the four measurements, with average values of 0.71(5) and 0.62(4) respectively. The calculations for transfer to the first resonance were found to be sensitive to the size of the energy bin used and therefore could not be used to extract a spectroscopic factor.Comment: 16 Pages, 10 figure

Evidence for Planet-induced Chromospheric Activity on HD 179949

We have detected the synchronous enhancement of Ca II H & K emission with the short-period planetary orbit in HD 179949. High-resolution spectra taken on three observing runs extending more than a year show the enhancement coincides with phi ~ 0 (the sub-planetary point) of the 3.093-day orbit with the effect persisting for more than 100 orbits. The synchronous enhancement is consistent with planet-induced chromospheric heating by magnetic rather than tidal interaction. Something which can only be confirmed by further observations. Independent observations are needed to determine whether the stellar rotation is sychronous with the planet's orbit. Of the five 51 Peg-type systems monitored, HD 179949 shows the greatest chromospheric H & K activity. Three others show significant nightly variations but the lack of any phase coherence prevents us saying whether the activity is induced by the planet. Our two standards, tau Ceti and the Sun, show no such nightly variations.Comment: 10 pages, 6 figures. Submitted to Ap

Interleukin-17A Mediates Acquired Immunity to Pneumococcal Colonization

Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell–dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1−/− mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-γ or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

A novel cardiovascular magnetic resonance risk score for predicting mortality following surgical aortic valve replacement

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936

The social construction of violence among Northern Plains tribal members with antisocial personality disorder and alcohol use disorder

Whereas recent reports from national studies have presented extremely high rates for many personality disorders in American Indian communities, persistent concerns about the meaning of these symptoms have left many troubled by these reports. American Indians as a group are known to suffer disproportionately from a number of violent experiences, but the dynamics of this violence have received little attention. This paper examines perspectives on violence in the lives of 15 northern plains tribal members who met criteria for antisocial personality disorder and comorbid alcohol use disorder. It explores how study participants constructed and understood their own violent encounters, as well as the motivations they described (characterized here as reputation, leveling, retaliation, catharsis, and self-defense). Violence was gendered in this study, with men generally presenting as perpetrators and women as victims. Men often described themselves as ready participants in a violent world, while women were quite clear that aggression for them was often simply required as they tried to defend themselves from male violence. While this analysis does not replace clinical analyses of violence in antisocial personality disorder, it does reveal an underlying cultural logic that may play a role in shaping the recourse to violence for that minority of individuals for whom it appears to be the obvious choice.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Regional and hemispheric influences on measured spring peroxyacetyl nitrate (PAN) mixing ratios at the Auchencorth UK EMEP supersite

AbstractThis work presents 15-min averaged measurements of peroxyacetyl nitrate (PAN) obtained during spring 2014 (24/04/2014 – 06/05/2014) at the Auchencorth UK EMEP supersite (southeast Scotland). The aim of this analysis was to investigate the conditions producing the distribution of PAN mixing ratios at the supersite in spring 2014. Air mass back trajectories showed the majority of air masses to have spent substantial time over the UK, continental Europe or Scandinavia prior to arrival at Auchencorth. The median and 95th percentile PAN mixing ratios observed were 0.46ppb and 1.03ppb, respectively. The median mixing ratio was elevated compared with previous PAN measurements during springtime (April–May) in southeast Scotland (corresponding median mixing ratios April–May 1994–1998: 0.1–0.3ppb), which is hypothesised to be due to conditions conducive to regional (European) photochemical PAN production. Additionally, PAN mixing ratios during regionally influenced conditions (0.4–1.5ppb) were substantially more elevated from hemispheric background mixing ratios (0.4–0.6ppb) than for ozone (O3, regional: 10–45ppb, hemispheric: 30–40ppb). PAN and O3 both impact upon vegetation and human health and it is necessary to understand the extent to which hemispheric and regional processes contribute to their abundances in different locations. Regional processes can both increase and decrease PAN and O3 mixing ratios compared to imported hemispheric background mixing ratios. This study concludes that during the measurement period in spring 2014 at the Auchencorth supersite, regional PAN and O3 modifying processes enhanced PAN mixing ratios more than for O3

Pneumococcal Capsular Polysaccharide Structure Predicts Serotype Prevalence

There are 91 known capsular serotypes of Streptococcus pneumoniae. The nasopharyngeal carriage prevalence of particular serotypes is relatively stable worldwide, but the host and bacterial factors that maintain these patterns are poorly understood. Given the possibility of serotype replacement following vaccination against seven clinically important serotypes, it is increasingly important to understand these factors. We hypothesized that the biochemical structure of the capsular polysaccharides could influence the degree of encapsulation of different serotypes, their susceptibility to killing by neutrophils, and ultimately their success during nasopharyngeal carriage. We sought to measure biological differences among capsular serotypes that may account for epidemiological patterns. Using an in vitro assay with both isogenic capsule-switch variants and clinical carriage isolates, we found an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing, and serotypes that were resistant to neutrophil-mediated killing tended to be more heavily encapsulated, as determined by FITC-dextran exclusion. Next, we identified a link between polysaccharide structure and carriage prevalence. Significantly, non-vaccine serotypes that have become common in vaccinated populations tend to be those with fewer carbons per repeat unit and low energy expended per repeat unit, suggesting a novel biological principle to explain patterns of serotype replacement. More prevalent serotypes are more heavily encapsulated and more resistant to neutrophil-mediated killing, and these phenotypes are associated with the structure of the capsular polysaccharide, suggesting a direct relationship between polysaccharide biochemistry and the success of a serotype during nasopharyngeal carriage and potentially providing a method for predicting serotype replacement