Antigen-presenting cells and antigen presentation in tertiary lymphoid organs

Tertiary lymphoid organs (TLOs) form in territorialized niches of peripheral tissues characterized by the presence of antigens; however, little is known about mechanism(s) of antigen handling by ectopic lymphoid structures. In this mini review, we will discuss the role of antigen-presenting cells and mechanisms of antigen presentation in TLOs, summarizing what is currently known about this facet of the formation and function of these tissues as well as identifying questions yet to be addressed

Development of primary invasive pneumococcal disease caused by serotype 1 pneumococci is driven by early increased type I interferon response in the lung

The pneumococcus is the world's foremost respiratory pathogen, but the mechanisms allowing this pathogen to proceed from initial asymptomatic colonization to invasive disease are poorly understood. We have examined the early stages of invasive pneumococcal disease (IPD) by comparing host transcriptional responses to an invasive strain and a noninvasive strain of serotype 1 Streptococcus pneumoniae in the mouse lung. While the two strains were present in equal numbers in the lung 6 h after intranasal challenge, only the invasive strain (strain 1861) had invaded the pleural cavity at that time point; this correlated with subsequent development of bacteremia in mice challenged with strain 1861 but not the noninvasive strain (strain 1). Progression beyond the lung was associated with stronger induction of the type I interferon (IFN-I) response in the lung at 6 h. Suppression of the IFN-I response through administration of neutralizing antibody to IFNAR1 (the receptor for type I interferons) led to significantly reduced invasion of the pleural cavity by strain 1861 at 6 h postchallenge. Our data suggest that strong induction of the IFN-I response is a key factor in early progression of invasive serotype 1 strain 1861 beyond the lung during development of IPD

The impact of pneumolysin on the macrophage response to Streptococcus pneumoniae is strain-dependent

Streptococcus pneumoniae is the world's leading cause of pneumonia, bacteremia, meningitis and otitis media. A major pneumococcal virulence factor is the cholesterol-dependent cytolysin, which has the defining property of forming pores in cholesterol-containing membranes. In recent times a clinically significant and internationally successful serotype 1 ST306 clone has been found to express a non-cytolytic variant of Ply (Ply306). However, while the pneumococcus is a naturally transformable organism, strains of the ST306 clonal group have to date been virtually impossible to transform, severely restricting efforts to understand the role of non-cytolytic Ply in the success of this clone. In this study isogenic Ply mutants were constructed in the D39 background and for the first time in the ST306 background (A0229467) to enable direct comparisons between Ply variants for their impact on the immune response in a macrophage-like cell line. Strains that expressed cytolytic Ply were found to induce a significant increase in IL-1β release from macrophage-like cells compared to the non-cytolytic and Ply-deficient strains in a background-independent manner, confirming the requirement for pore formation in the Ply-dependent activation of the NLRP3 inflammasome. However, cytolytic activity in the D39 background was found to induce increased expression of the genes encoding GM-CSF (CSF2), p19 subunit of IL-23 (IL23A) and IFNβ (IFNB1) compared to non-cytolytic and Ply-deficient D39 mutants, but had no effect in the A0229467 background. The impact of Ply on the immune response to the pneumococcus is highly dependent on the strain background, thus emphasising the importance of the interaction between specific virulence factors and other components of the genetic background of this organism

Isolation site influences virulence phenotype of serotype 14 Streptococcus pneumoniae strains belonging to multilocus sequence type 15

Streptococcus pneumoniae is a diverse species causing invasive as well as localized infections that result in massive global morbidity and mortality. Strains vary markedly in pathogenic potential, but the molecular basis is obscured by the diversity and plasticity of the pneumococcal genome. We have previously reported that S. pneumoniae serotype 3 isolates belonging to the same multilocus sequence type (MLST) differed markedly in in vitro and in vivo phenotypes, in accordance with the clinical site of isolation, suggesting stable niche adaptation within a clonal lineage. In the present study, we have extended our analysis to serotype 14 clinical isolates from cases of sepsis or otitis media that belong to the same MLST (ST15). In a murine intranasal challenge model, five ST15 isolates (three from blood and two from ears) colonized the nasopharynx to similar extents. However, blood and ear isolates exhibited significant differences in bacterial loads in other host niches (lungs, ear, and brain) at both 24 and 72 h postchallenge. In spite of these differences, blood and ear isolates were present in the lungs at similar levels at 6 h postchallenge, suggesting that early immune responses may underpin the distinct virulence phenotypes. Transcriptional analysis of lung tissue from mice infected for 6 h with blood isolates versus ear isolates revealed 8 differentially expressed genes. Two of these were exclusively expressed in response to infection with the ear isolate. These results suggest a link between the differential capacities to elicit early innate immune responses and the distinct virulence phenotypes of clonally related S. pneumoniae strains

Overlapping functionality of the Pht proteins in zinc homeostasis of streptococcus pneumoniae

Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress

The first histidine triad motif of phtd is critical for zinc homeostasis in Streptococcus pneumoniae

Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino- and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence

Microplastics in the Antarctic marine system: An emerging area of research

It was thought that the Southern Ocean was relatively free of microplastic contamination; however, recent studies and citizen science projects in the Southern Ocean have reported microplastics in deep-sea sediments and surface waters. Here we reviewed available information on microplastics (including macroplastics as a source of microplastics) in the Southern Ocean. We estimated primary microplastic concentrations from personal care products and laundry, and identified potential sources and routes of transmission into the region. Estimates showed the levels of microplastic pollution released into the region from ships and scientific research stations were likely to be negligible at the scale of the Southern Ocean, but may be significant on a local scale. This was demonstrated by the detection of the first microplastics in shallow benthic sediments close to a number of research stations on King George Island. Furthermore, our predictions of primary microplastic concentrations from local sources were five orders of magnitude lower than levels reported in published sampling surveys (assuming an even dispersal at the ocean surface). Sea surface transfer from lower latitudes may contribute, at an as yet unknown level, to Southern Ocean plastic concentrations. Acknowledging the lack of data describing microplastic origins, concentrations, distribution and impacts in the Southern Ocean, we highlight the urgent need for research, and call for routine, standardised monitoring in the Antarctic marine system

Interpretations of Lava Flow Properties from Radar Remote Sensing Data

The surface morphology and roughness of a lava flow provides insight on its lava properties and emplacement processes. This is essential information for understanding the eruption history of lava fields, and magmatic processes beneath the surface of Earth and other planetary bodies such as the Moon. The surface morphology is influenced by lava properties such as viscosity, temperature, composition, and rate of shear. In this work, we seek to understand how we can interpret the emplacement processes and lava properties of lava flows using remote sensing data. Craters of the Moon (COTM) National Monument and Preserve in Idaho hosts a suite of compositionally diverse lava flows with a wide range of surface roughness making it the ideal case study. Lava flows there have surface morphologies consistent with smooth pāhoehoe, slabby pāhoehoe, hummocky pāhoehoe, rubbly pāhoehoe, ‘a’ā, block-`a’ā, and blocky textures. The variation in surface roughness across the lava field reflects changes in lava properties and/or emplacement processes over space and time. We investigate geochemical and petrographic variations of the different lava flow morphologies and analyse how they relate to airborne radar data. Results show L-Band (24 cm) radar circular polarization ratios (CPR) distinguish the contrasting surface roughness at COTM, separating the smoother (primitive; low SiO2 and alkali) and rougher (evolved; high SiO2 and alkali) lava flows. However, ambiguities are present when comparing the CPR values for rubbly pāhoehoe and block-`a’ā flow. Even though their CPR values appear similar at the decimetre scale, they have distinct morphologies that formed under different emplacement processes. Without ground-truth information, the rubbly pāhoehoe and block-`a’ā lava flows could therefore be misinterpreted to be the same type of flow morphology, which would lead to false interpretations about their lava properties and emplacement processes. This is important when comparing these flows to lava flows on other planetary bodies that share similar CPR values, such as the Moon. Thus, using terrestrial analogues such as those at COTM can provide an improved understanding of the surface morphology and emplacement processes of lunar lava flows. This will lead to more refined interpretations about past volcanic processes on the Moon

GRADE-ADOLOPMENT process to develop 24-hour movement behavior recommendations and physical activity guidelines for the under 5s in the United Kingdom, 2019

Background: This article summarizes the approach taken to develop UK Chief Medical Officers' physical activity guidelines for the Under 5s, 2019. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE)- Adaptation, Adoption, De Novo Development (ADOLOPMENT) approach was used, based on the guidelines from Canada and Australia, with evidence updated to February 2018. Recommendations were based on the associations between (1) time spent in sleep, sedentary time, physical activity, and 10 health outcomes and (2) time spent in physical activity and sedentary behavior on sleep outcomes (duration and latency). Results: For many outcomes, more time spent in physical activity and sleep (up to a point) was beneficial, as was less time spent in sedentary behavior. The authors present, for the first time, evidence in GRADE format on behavior type-outcome associations for infants, toddlers, and preschoolers. Stakeholders supported all recommendations, but recommendations on sleep and screen time were not accepted by the Chief Medical Officers; UK guidelines will refer only to physical activity. Conclusions: This is the first European use of GRADE-ADOLOPMENT to develop physical activity guidelines. The process is robust, rapid, and inexpensive, but the UK experience illustrates a number of challenges that should help development of physical activity guidelines in future