Infection dynamics: from organ to host population

A symposium discussing collaborative research work on infectious diseases dynamics was held at Queens' College, University of Cambridge on 25 October 2006

Clustered Intracellular Salmonella enterica Serovar Typhimurium blocks host cell cytokinesis

Several bacterial pathogens and viruses interfere with the cell cycle of their host cells to enhance virulence. This is especially apparent in bacteria that colonize the gut epithelium, where inhibition of the cell cycle of infected cells enhances the intestinal colonization. We found that intracellular Salmonella enterica serovar Typhimurium induced the binucleation of a large proportion of epithelial cells by 14 h postinvasion and that the effect was dependent on an intact Salmonella pathogenicity island 2 (SPI-2) type 3 secretion system. The SPI-2 effectors SseF and SseG were required to induce binucleation. SseF and SseG are known to maintain microcolonies of Salmonella-containing vacuoles close to the microtubule organizing center of infected epithelial cells. During host cell division, these clustered microcolonies prevented the correct localization of members of the chromosomal passenger complex and mitotic kinesin-like protein 1 and consequently prevented cytokinesis. Tetraploidy, arising from a cytokinesis defect, is known to have a deleterious effect on subsequent cell divisions, resulting in either chromosomal instabilities or cell cycle arrest. In infected mice, proliferation of small intestinal epithelial cells was compromised in an SseF/SseG-dependent manner, suggesting that cytokinesis failure caused by S. Typhimurium delays epithelial cell turnover in the intestine

Healthcare-associated outbreak of meticillin-resistant Staphylococcus aureus bacteraemia: role of a cryptic variant of an epidemic clone

BACKGROUND New strains of meticillin-resistant Staphylococcus aureus (MRSA) may be associated with changes in rates of disease or clinical presentation. Conventional typing techniques may not detect new clonal variants that underlie changes in epidemiology or clinical phenotype. AIM To investigate the role of clonal variants of MRSA in an outbreak of MRSA bacteraemia at a hospital in England. METHODS Bacteraemia isolates of the major UK lineages (EMRSA-15 and -16) from before and after the outbreak were analysed by whole-genome sequencing in the context of epidemiological and clinical data. For comparison, EMRSA-15 and -16 isolates from another hospital in England were sequenced. A clonal variant of EMRSA-16 was identified at the outbreak hospital and a molecular signature test designed to distinguish variant isolates among further EMRSA-16 strains. FINDINGS By whole-genome sequencing, EMRSA-16 isolates during the outbreak showed strikingly low genetic diversity (P < 1 × 10(-6), Monte Carlo test), compared with EMRSA-15 and EMRSA-16 isolates from before the outbreak or the comparator hospital, demonstrating the emergence of a clonal variant. The variant was indistinguishable from the ancestral strain by conventional typing. This clonal variant accounted for 64/72 (89%) of EMRSA-16 bacteraemia isolates at the outbreak hospital from 2006. CONCLUSIONS Evolutionary changes in epidemic MRSA strains not detected by conventional typing may be associated with changes in disease epidemiology. Rapid and affordable technologies for whole-genome sequencing are becoming available with the potential to identify and track the emergence of variants of highly clonal organisms

Proximity induced metal/insulator transition in YBa2Cu3O7/La2/3Ca1/3MnO3Y Ba_2 Cu_3 O_7 / La_{2/3} Ca_{1/3} Mn O_3 superlattices

The far-infrared dielectric response of superlattices (SL) composed of superconducting YBa$_{2}$Cu$_{3}$O$_{7}$ (YBCO) and ferromagnetic La$_{0.67}$% Ca$_{0.33}$MnO$_{3}$ (LCMO) has been investigated by ellipsometry. A drastic decrease of the free carrier response is observed which involves an unusually large length scale of d$^{crit}\approx$20 nm in YBCO and d$^{crit}\approx$10 nm in LCMO. A corresponding suppression of metallicity is not observed in SLs where LCMO is replaced by the paramagnetic metal LaNiO$_{3}$. Our data suggest that either a long range charge transfer from the YBCO to the LCMO layers or alternatively a strong coupling of the charge carriers to the different and competitive kind of magnetic correlations in the LCMO and YBCO layers are at the heart of the observed metal/insulator transition. The low free carrier response observed in the far-infrared dielectric response of the magnetic superconductor RuSr$_{2}$GdCu$_{2}$O$_{8}$ is possibly related to this effect

Deep hanging out in the arts: an anthropological approach to capturing cultural value

This article presents the findings of an Arts and Humanities Research Council (AHRC) funded project carried out from September 2013 to March 2014 by five researchers at the University of Leeds (UK), who paired off with five audience-participants and engaged in a process of “deep hanging out” (Geertz 1998) at events curated as part of Leeds’ annual LoveArts festival. As part of AHRC’s Cultural Value project, the overarching aim of the research was to produce a rich, polyvocal, evocative and complex account of cultural value by co-investigating arts engagement with audience-participants. Findings suggested that both the methods and purpose of knowing about cultural value impact significantly on any exploration of cultural experience. Fieldwork culminated in the apparent paradox that we know, and yet still don’t seem to know, the value and impact of the arts. Protracted discussions with the participants suggested that this paradox stemmed from a misplaced focus on knowledge; that instead of striving to understand and rationalize the value of the arts, we should instead aim to feel and experience it. During a process of deep hanging out, our participants revealed the limitations of language in capturing the value of the arts, yet confirmed perceptions of the arts as a vehicle for developing self-identity and -expression and for living a better life. These findings suggest that the Cultural Value debate needs to be reframed from what is currently an interminable epistemological obsession (that seeks to prove and evidence the value of culture) into a more complex phenomenological question, which asks how people experience the arts and culture and why people want to understand its value. This in turn implies a re-conceptualization of the relationships between artists or arts organisations and their publics, based on a more relational form of engagement and on a more anthropological approach to capturing and co-creating cultural value

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Stability of purgeable VOCs in water samples during pre-analytical holding. Part 2: Analyses by an EPA regional laboratory

This study was undertaken to examine the hypothesis that prevalent and priority purgeable VOCs in properly preserved water samples are stable for at least 28 days. For the purposes of this study, VOCs were considered functionally stable if concentrations measured after 28 days did not change by more than 10% from the initial values. An extensive stability experiment was performed on freshly-collected surface water spiked with a suite of 44 purgeable VOCs. The spiked water was then distributed into multiple 40-mL VOC vials with 0.010-in Teflon-lined silicone septum caps prefilled with 250 mg of NaHSO{sub 4} (resulting pH of the water {approximately}2). The samples were sent to a commercial [Analytical Resources, Inc. (ARI)] and EPA (Region IV) laboratory where they were stored at 4 C. On 1, 8, 15, 22, 29, 36, and 71 days after sample preparation, analysts from ARI took 4 replicate samples out of storage and analyzed these samples for purgeable VOCs following EPA/SW846 8260A. A similar analysis schedule was followed by analysts at the EPA laboratory. This document contains the results from the EPA analyses; the ARI results are described in a separate report

Polynucleotide Phosphorylase Negatively Controls spv Virulence Gene Expression in Salmonella enterica

Mutational inactivation of the cold-shock-associated exoribonuclease polynucleotide phosphorylase (PNPase; encoded by the pnp gene) in Salmonella enterica serovar Typhimurium was previously shown to enable the bacteria to cause chronic infection and to affect the bacterial replication in BALB/c mice (M. O. Clements et al., Proc. Natl. Acad. Sci. USA 99:8784-8789, 2002). Here, we report that PNPase deficiency results in increased expression of Salmonella plasmid virulence (spv) genes under in vitro growth conditions that allow induction of spv expression. Furthermore, whole-genome microarray-based transcriptome analyses of bacteria growing inside murine macrophage-like J774.A.1 cells revealed six genes as being significantly up-regulated in the PNPase-deficient background, which included spvABC, rtcB, entC, and STM2236. Mutational inactivation of the spvR regulator diminished the increased expression of spv observed in the pnp mutant background, implying that PNPase acts upstream of or at the level of SpvR. Finally, competition experiments revealed that the growth advantage of the pnp mutant in BALB/c mice was dependent on spvR as well. Combined, our results support the idea that in S. enterica PNPase, apart from being a regulator of the cold shock response, also functions in tuning the expression of virulence genes and bacterial fitness during infection