Control of regulatory T cell activity by endogenous and pathogen-derived EGFR ligand

Regulatory T cells (Treg) are CD4+ FOXP3+ T lymphocytes whose function is to prevent autoimmunity and immune cell-mediated damage on infected tissues. They carry out their suppressive effects either by direct cell-cell contact or through the use of soluble mediators such as IL-10 and TGFb. Activated Treg express the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor found in most tissue types and leukocytes. EGFR signalling induces behavioural changes in Treg: in particular, the ligand Amphiregulin (AREG) is required for optimal Treg function in various in- vitro and in-vivo experimental models. The aim of my thesis has been to explore the effects of EGFR signalling on Treg function in the context of infection, induced either from endogenously expressed or pathogen-derived ligands. In Chapter 2 I examined the effects of Vaccinia (VACV) virus-derived Vaccinia Growth Factor (VGF), a pathogen-derived soluble protein with EGF-like activity, on Treg function. I showed that Treg function is increased when exposed to UV- inactivated Vaccinia virus, but that this activation can be blocked by deleting EGFR expression on Treg. Using an in-vivo pneumonitis model, I showed that mice deficient in EGFR expression on their Tregs were more resistant to VACV infection compared to wildtype, and that following infection there was less bioactive TGFb in the bronchoalveolar lavage supernatant of these animals. Taken together, these data imply that Vaccinia virus derived VGF enhances the suppressive capacity of Tregs and use this enhanced activation as a means of immune escape. In Chapter 3 I used the filariasis model Litomosoides sigmodontis (a chronic helminth infection of rodents) to examine the effects of EGFR signalling in Tregs induced by the endogenous ligand Amphiregulin, and to study the effects of EGFR blockade on the helminth-specific immune response using the commercially available tyrosine kinase inhibitor Gefitinib. We found that EGFR deletion on Treg lead to no increase in TH2 cytokine production or parasite rejection. Also, complete deletion of Amphiregulin in Areg-/- mice had no significant effect; nor did the administration of Gefitinib over several weeks in WT mice. From these findings, we conclude that AREG-EGFR signalling on Tregs (or EGFR signalling in general) is not a significant factor influencing the immune response to L.sigmodontis infection. In Chapter 4 I examined the effects of the complete deletion of Amphiregulin in Areg-/- mice, and the deletion of Amphiregulin in specific cell types, on the activity of activated Tregs in an airway allergy model. To induce and activate Tregs we used the murine helminth Heligmosomoides polygyrus, which infects the gastrointestinal tract but also induces Treg expansion systemically. Previous work in our group had determined that Amphiregulin deletion in mice led to a decreased Treg-mediated immunosuppression following H. polygyrus infection and airway OVA challenge, as evidenced by greater eosinophilia in the lungs of Areg-/- than wildtype mice. However, I failed to replicate the initial findings of our group’s work, seeing no difference in Treg activity or TH2 response between infected and noninfected animals, and also no significant differences in different mouse strains with a cell type-specific deletion of Amphiregulin. Taken together, my thesis provides evidence for the enhanced suppressive capacity of Tregs by a viral pathogen derived EGFR ligand, in order to create a local immunosuppressive environment. To our knowledge, this is the very first time such an immune escape mechanism has been demonstrated. It also demonstrates that in the face of helminth-mediated activation of Treg, EGFR signalling is not a significant factor contributing to local immune suppression. This further clarifies the role of EGFR signalling on Tregs in the setting of both acute and chronic infection

Estimation of Atmospheric Turbulence Using Differential Motion of Extended Features in Time-lapse Imagery

We address the design, development, and testing of a pointer/tracker as a probe beam for the purpose of making high-speed, aero-optical measurements of the flow over a scaled beam director turret. The tracker uses retro-reflection of the probe beam off of a Reflexite annulus surrounding the turret. The constraints of the design required a near-total-commercial off the shelf system that could be quickly installed and removed in a rented aircraft. Baseline measurements of environmental vibrations are used to predict pointing performance; mitigation of line-of-sight jitter on the probe beam is achieved through passive isolation and the design of relay optics. Accommodation of ambient light is made with the use of wavelength filters and track algorithms. Postanalysis of measured data is compared to design estimates

Individual differences in loss aversion: conscientiousness predicts how life satisfaction responds to losses versus gains in income

Loss aversion is considered a general pervasive bias occurring regardless of context or person making the decision. We hypothesized that conscientiousness would predict an aversion to losses in the financial domain. We index loss aversion by the relative impact of income losses and gains on life satisfaction. In a representative German sample (N¬ = 105,558: replicated in a British sample, N = 33,848), with conscientiousness measured at baseline, those high on conscientiousness have the strongest reactions to income losses, suggesting a pronounced loss aversion effect, whilst for those moderately un-conscientious there is no loss aversion effect. Our research; (a) provides the first evidence of personality moderation of any loss aversion phenomena; (b) supports contextual perspectives that both personality and situational factors need to be examined in combination; (c) shows that the small but robust relationship with life satisfaction is primarily driven by a subset of people experiencing highly impactful losses

Genomic assembly of clinical Candida glabrata (Nakaseomyces glabrata) isolates reveals within-species structural plasticity and association with In Vitro antifungal susceptibility

The opportunistic human pathogen Candida glabrata has become an increasingly important threat to human health, with infections globally characterized by high mortality rates and multidrug resistance. To face this threat, more efficient diagnostic and therapeutic approaches are required, underpinning research to help define the intraspecies epidemiology, genetic variability, and therefore, diagnostic and therapeutic target stability. Previous comparative genetics studies conducted on limited numbers of strains only revealed partial resolution of chromosomal settings. In this study, by combining short- and long-read genome sequencing, phenotypic characterization, and comparative genomics over a large set of strains, we detected strict relationships between large chromosomal rearrangements and phylogenetic clades, genes subjected to different selective pressures, and new sets of genes associated with resistance to antifungals. Overall, these results not only provide a fundamental contribution to our knowledge of C. glabrata evolution and epidemiology but may also lay the foundations for the future development of tailored therapeutic approaches

Type 2 inflammation in eosinophilic chronic obstructive pulmonary disease

From Wiley via Jisc Publications RouterHistory: received 2020-10-12, rev-recd 2020-10-28, accepted 2020-11-11, pub-electronic 2020-12-05, pub-print 2021-06Article version: VoRPublication status: PublishedFunder: NIHR Manchester Biomedical Research Centre; Id: http://dx.doi.org/10.13039/10001465

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

RATIONALE: Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and antipathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD. We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights into potential disease mechanisms. METHODS: Bronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed. RESULTS: Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD versus controls (log2 fold change (log2FC) -2.0, -2.2, -1.5, -0.5, -0.7 and -0.5 (adjusted p<0.02), respectively) and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D, napsin A and CD44 inversely correlated with computed tomography small airways disease measures (expiratory to inspiratory mean lung density) (r= -0.56, r= -0.58, r= -0.45, r= -0.36, r= -0.44, r= -0.37, r= -0.40 and r= -0.39 (adjusted p<0.05)). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (% low-attenuation areas): r= -0.55, r= -0.61, r= -0.48, r= -0.51, r= -0.41, r= -0.31 and r= -0.34, respectively (adjusted p<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated in COPD versus controls (log2FC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD versus healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85). CONCLUSIONS: Using a multiomics approach, we demonstrate, for the first time, global surfactant dysregulation in COPD that was associated with emphysema, giving new insights into potential mechanisms underlying the cause or consequence of disease

Process account of curiosity and interest: a reward-learning perspective

Previous studies suggested roles for curiosity and interest in knowledge acquisition and exploration, but there has been a long-standing debate about how to define these concepts and whether they are related or different. In this paper, we address the definition issue by arguing that there is inherent difficulty in defining curiosity and interest, because both curiosity and interest are naïve concepts, which are not supposed to have a priori scientific definitions. We present a reward-learning framework of autonomous knowledge acquisition and use this framework to illustrate the importance of process account as an alternative to advance our understanding of curiosity and interest without being troubled by their definitions. The framework centers on the role of rewarding experience associated with knowledge acquisition and learning and posits that the acquisition of new knowledge strengthens the value of further information. Critically, we argue that curiosity and interest are the concepts that they subjectively construe through this knowledge-acquisition process. Finally, we discuss the implications of the reward-learning framework for education and empirical research in educational psychology