Biology subjects

Donovan, C.

Publications and source records attributed to Donovan, C..

4 recordsLinked to original sources

bioRxiv2025

Crucial role for iron metabolism in mediating influenza A virus infection and associated disease

Rationale and ObjectivesIron availability and metabolism are important in the pathogenesis of bacterial infections. More recently, links have been reported between iron and the severity of viral infections. In this study, we characterize a crucial relationship between iron metabolism and IAV infection and disease. MethodsIron-related gene expression was assessed in human airway epithelial cells (AEC) infected with IAV. AECs were cultured with ferric iron, iron-loaded transferrin, or iron chelator, deferoxamine (DFO), prior to infection with IAV. Mice were placed on a high iron diet for 8 weeks prior to infection with IAV or treated with anti-transferrin receptor-1 (TFR1) antibody during IAV infection. The effects of iron modulation and depletion of TFR1-mediated responses on IAV infection were assessed. Measurements and main resultsIron-related gene expression and metabolism are altered systemically and in lung tissues and AECs during IAV infections. Increasing iron availability increases viral titer in AECs, while DFO protects against iron-induced increased susceptibility to infection. Increasing systemic iron loading, which increases iron levels in the lung, increases viral titer, proinflammatory responses, airway inflammation, and worsens IAV-induced disease in terms of lung function and weight loss in vivo. Inhibition of TFR1 protects against IAV-induced disease in vivo. ConclusionIAV infections remain a major threat to human health and global economies. Strategies that boost protective, or reduce pathogenic, host responses may provide broadly effective, long-term therapeutic options. We have identified a key role for iron metabolism in modifying host responses to IAV that can be harnessed to protect against disease. Key MessagesO_LIIron metabolism is altered systemically, and in airway epithelial cells and lung tissues, during IAV infection. C_LIO_LIIncreased iron availability increases viral titer both in vitro and in vivo C_LIO_LISystemic iron loading worsens IAV-induced inflammation and disease outcomes in vivo, highlighting iron as a crucial factor for modulating IAV infections and disease. C_LIO_LIHost epithelial cells and lung tissues reduce TFRC gene expression, whilst the number and proportion of TFR1hi expressing cells increase, in response to IAV infection. Neutralising TFR1 protects against IAV-induced disease in vivo, highlighting TFR1 as a potential therapeutic target for IAV infections. C_LI

immunology↗

bioRxiv2023

Fecal microbial transfer and complex carbohydrates mediate protection against COPD

ObjectiveChronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DesignUsing an in vivo mouse model of cigarette smoke-induced COPD and fecal microbial transfer (FMT), we characterized the fecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology, and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in sixteen COPD patients using a randomized, double-blind, placebo-controlled pilot study of inulin supplementation. ResultsFMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in cigarette smoke-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. ConclusionThe gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically. What is already known on this topicO_LIChanges in gut microbiota are associated with COPD but the underlying host and microbial mechanisms are unclear, limiting the therapeutic applications. C_LI What this study addsO_LIMicrobiome composition and metabolism is reproducibly correlated with lung and gastrointestinal pathology in experimental COPD. C_LIO_LIMicrobiome modifying interventions effectively alleviate disease, including protective effects supplementing smoking cessation. C_LIO_LINutritional interventions targeting the microbiome in COPD patients demonstrate efficacy in a small pilot study. C_LI How this study might affect research, practice or policyO_LIMicrobiome-targeting therapeutics and nutritional interventions may be developed for COPD, including as supplements to smoking cessation. C_LI

physiology↗

bioRxiv2020

Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with a significant number of patients being inadequately controlled by current frontline treatments means that there is a need to define novel therapeutic targets for these conditions1. Here we investigate a member of the G protein-coupled receptor (GPCR) family, FFA4, which responds to free circulating fatty acids, including dietary omega-3 fatty acids found in fish oils2–4. Although usually associated with metabolic responses linked with food intake, we show that FFA4 is expressed in the lung where it is coupled to Gq/11-signalling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated, at least in part, by the release of the prostaglandin PGE2 that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. Importantly, in acute and chronic ozone models of pollution-mediated inflammation, and in house-dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, whilst this response was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was very similar to that observed in mice and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation. Hence, our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy that might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2016

Novel chromosome organization pattern in actinomycetales-overlapping replication cycles combined with diploidy

Bacteria regulate chromosome replication and segregation tightly with cell division to ensure faithful segregation of DNA to daughter generations. The underlying mechanisms have been addressed in several model species. It became apparent that bacteria have evolved quite different strategies to regulate DNA segregation and chromosomal organization. We have investigated here how the actinobacterium Corynebacterium glutamicum organizes chromosome segregation and DNA replication. Unexpectedly, we find that C. glutamicum cells are at least diploid under all conditions tested and that these organisms have overlapping C-periods during replication with both origins initiating replication simultaneously. Based on experimentally obtained data we propose growth rate dependent cell cycle models for C. glutamicum.

microbiology↗