Explore the vast range of titles available.

Human cytomegalovirus (HCMV) is a β-herpesvirus with high sero-prevalence within the human population. Primary HCMV infection and life-long carriage are typically asymptomatic. However, HCMV is implicated in exacerbation of chronic conditions and associated damage in individuals with intact immune systems. Furthermore, HCMV is a significant cause of morbidity and mortality in the immunologically immature and immune-compromised where disease is associated with tissue damage. Infection-induced inflammation, including robust cytokine responses, is a key component of pathologies associated with many viruses. Despite encoding a large number of immune-evasion genes, HCMV also triggers the induction of inflammatory cytokine responses during infection. Thus, understanding how cytokines contribute to CMV-induced pathologies and the mechanisms through which they are regulated may inform clinical management of disease. Herein, we discuss our current understanding based on clinical observation and modeling of disease of the role that cytokines play in CMV pathogenesis. Specifically, in the context of the different tissues and organs in which CMV replicates, we give a broad overview of the beneficial and adverse effects that cytokines have during infection and describe how cytokine-mediated tissue damage is regulated. We discuss the implications of findings derived from mice and humans for therapeutic intervention strategies and our understanding of how host genetics may influence the outcome of CMV infections.

CuFeO 2 is a promising photocathode for H 2 evolution and CO 2 reduction reactions. To better understand the complex defect chemistry and role of impurity phases in this material and their effect on the photochemical performance, we employ visible light transient absorption spectroscopy and density functional theory (DFT) calculations to investigate the electron dynamics in electrochemically deposited Cu-Fe oxide thin films. Kinetic analysis of carrier lifetime shows a fast, sub-ps contribution to relaxation followed by persistence of a long-lived state to time delays greater than 2 ns. Increasing amplitude of the long-lived state is shown to correlate with the rate of fast initial relaxation, and this is explained in terms of a competition between charge carrier trapping and charge separation. Charge separation in CuFeO 2 occurs via hole thermalization from O 2p to Cu 3d valence band states leading to segregation of electrons and holes across layers in the CuFeO 2 lattice. Correlation between transient absorption measurements and DFT calculations suggest that Cu vacancies enhance photochemical performance by facilitating charge separation kinetics. In contrast, O interstitials are predicted to switch the relative positions of O 2p and Cu 3d valence band states, which would inhibit charge separation by inter-band hole thermalization. Finally, we find no evidence for electron injection from CuFeO 2 to CuO suggesting that charge separation at this heterostructure interface does not play a role in the carrier lifetime or photochemical performance of the catalysts studied here.

In this analysis, we systematically review and synthesize the results of two local-level studies linking various types of carbon emissions data with nationwide measures of affluence. We focus on the socio-economic dimensions of climate policy, differentiating between different sources of greenhouse gas emissions, and between different methods of collecting greenhouse gas emissions data. We demonstrate that high levels of affluence spatially displace carbon-intensive production-based emissions. We then synthesize a framework for future research on environmental policy design to explicitly consider the method of collecting data on carbon emissions by sector and activity. We offer strategies for policymakers regarding the conditions under which specific carbon emissions data collection methods may be more relevant or appropriate than other methods. We emphasize that more equitable environmental policy objectives can be achieved by recognizing the socio-economic dimensions of carbon emissions data, thus the importance of critically examining the way those data inform policy.

Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.

Human cytomegalovirus (HCMV) causes significant disease in individuals with impaired or immature immune systems, such as transplant patients and after congenital infection. Antiviral drugs that target the virus directly are toxic and are susceptible to antiviral drug resistance due to virus mutations. An alternate strategy is to target processes within host cells that are required by the virus for replication. Herein, we show that HCMV infection triggers a highly reactive molecule, peroxynitrite, during the initial stages of infection. Peroxynitrite was required for the initial entry of the virus into the cell and promotes virus replication in multiple cell types, suggesting a broad pro-viral function. Importantly, targeting peroxynitrite dramatically inhibited cytomegalovirus replication in cells in the laboratory and in mice, suggesting that therapeutic targeting of this molecule and/or the cellular functions it regulates could represent a novel strategy to inhibit HCMV infection.

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.

Inhibitory CD4 + T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4 + T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated T H 1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L -arginine. Mice lacking Arg1-expressing CD4 + T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4 + lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4 + T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1.

Interferon lambda (IFNλ) is a group of cytokines that belong to the IL-10 family. They exhibit antiviral activities against certain viruses during infection of the liver and mucosal tissues. Here we report that IFNλ restricts in vitro replication of the β-herpesvirus murine cytomegalovirus (mCMV). However, IFNλR1-deficient (Ifnλr1-/-) mice were not preferentially susceptible to mCMV infection in vivo during acute infection after systemic or mucosal challenge, or during virus persistence in the mucosa. Instead, our studies revealed that IFNλ influences NK cell responses during mCMV infection. Ifnλr1-/- mice exhibited defective development of conventional interferon-gamma (IFNγ)-expressing NK cells in the spleen during mCMV infection whereas accumulation of granzyme B-expressing NK cells was unaltered. In vitro, development of splenic IFNγ+ NK cells following stimulation with IL-12 or, to a lesser extent, IL-18 was abrogated by IFNλR1-deficiency. Thus, IFNλ regulates NK cell responses during mCMV infection and restricts virus replication in vitro but is redundant in the control of acute and persistent mCMV replication within mucosal and non-mucosal tissues.

Human cytomegalovirus (HCMV) is a ubiquitous member of the herpesvirus family, of significant clinical importance, and highly adapted to its host, resulting from millions of years of co-evolution. As a result, the virus systematically subverts almost all aspects of antiviral immune defence to successfully establish a lifelong persistent infection, and in the process, dramatically reshapes the phenotype and function of host immunity to both HCMV and other diseases. Natural killer (NK) cells are a critical component of successful herpesvirus control. Here, we discuss their role in modulating HCMV disease and the multitude of ways that HCMV has evolved to prevent and manipulate this process. We also consider how antibody-dependent cellular cytotoxicity by NK cells directed against HCMV might overcome NK immune evasion mechanisms and be useful therapeutically.

Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.