Philip M. Hansbro

Description:Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death worldwide [Citation1–4]. It is characterized by progressive chronic bronchial inflammation that induces small airway remodeling and lung tissue damage in alveoli with emphysema, resulting in severe breathing difficulties [Citation5]. Cigarette smoke (CS) inhalation is the primary cause of this disease. Other causes and risk factors include air pollution, indoor cooking, occupational exposure, and genetics. Patients with COPD patients have increased susceptibility to bacterial and viral infections, causing symptom exacerbation infections [Citation5–9]. There is no cure for COPD, and available treatments only improve the symptoms. This is primarily due to the lack of understanding of the mechanisms involved in COPD pathogenesis. This has been largely due to the absence of short-term mouse models of cigarette smoke-induced COPD that accurately recapitulate the hallmark features of the human disease. Improving our understanding of how COPD develops, progresses and is exacerbated is critical for exploring novel treatments for the disease. Mast cells are a type of innate immune cells that play an important role in the immune system and respond to allergens, pathogens, and foreign particles [Citation10]. These cells are located in connective tissues of the lungs and are involved in the pathogenesis of chronic inflammatory lung diseases, such as COPD. Mast cells can make mediators of their function de novo and contain many granules with pre-formed mediators such as histamines, cytokines, chemokines, and proteases [Citation11]. These granules are released when the mast cells respond to foreign particles and pathogens, in a process termed degranulation [Citation11]. Chymases and tryptases are two of the most important mast cell proteases. Our previous studies showed that their gene expression is increased in the lungs of COPD patients [Citation12,Citation13]. However, the mechanisms underlying the contributions of mast cell proteases in the pathological processes of COPD remain poorly understood. We recently elucidated the roles of mast cell chymases and tryptases in driving chronic inflammation-induced lung damage and emphysema in COPD [Citation12,Citation14–16]. Targeting these molecules may be an effective and urgently needed novel therapeutic option for this debilitating lung disease.

Description:Preeclampsia is a complex pregnancy disorder characterized by the new onset of hypertension and organ dysfunction, often leading to significant maternal and fetal morbidity and mortality. Placental dysfunction is a hallmark feature of preeclampsia, which is often caused by inappropriate trophoblast cell function in association with oxidative stress, inflammation and/or pathological hypoxia. This study explores the role of oxidative stress in trophoblast cell-based models mimicking the preeclamptic placenta and evaluates potential therapeutic strategies targeting these mechanisms. Uric acid (UA) and malondialdehyde (MDA) concentrations were measured in human plasma from women with preeclampsia (n = 24) or normotensive controls (n = 14) using colorimetric assays. Custom-made first trimester trophoblast cell line, ACH-3P, was exposed to various preeclampsia-like stimuli including hypoxia mimetic (dimethyloxalylglycine or DMOG, 1 mM), inflammation (tumour necrosis factor or TNF-α, 10 ng/mL) or mitochondria dysfunction agent, (Rhodamine-6G or Rho-6G, 1 μg/mL), ± aspirin (0.5 mM), metformin (0.5 mM), AD-01 (100 nM) or resveratrol (15 µM), for 48 h. Following treatments, UA/MDA, proliferation (MTT), wound scratch and cytometric bead, assays, were performed. Overall, MDA plasma concentration was increased in the preeclampsia group compared to healthy controls (p < 0.001) whereas UA showed a trend towards an increase (p = 0.06); when adjusted for differences in gestational age at blood sampling, MDA remained (p < 0.001) whereas UA became (p = 0.03) significantly correlated with preeclampsia. Our 2D first trimester trophoblast cell-based in vitro model of placental stress as observed in preeclampsia, mimicked the increase in UA concentration following treatment with DMOG (p < 0.0001), TNF-α (p < 0.05) or Rho-6G (p < 0.001) whereas MDA cell concentration increased only in the presence of DMOG (p < 0.0001) or Rho-6G (p < 0.001). Metformin was able to abrogate DMOG- (p < 0.01), Rho-6G- (p < 0.0001) or TNF-α- (p < 0.01) induced increase in UA, or DMOG- (p < 0.0001) or TNF-α- (p < 0.05)induced increase in MDA. AD-01 abrogated UA or MDA increase in the presence of TNF-α (p < 0.001) or Rho-6G (p < 0.001)/DMOG (p < 0.0001), respectively. The preeclampsia-like stimuli also mimicked adverse impact on trophoblast cell proliferation, migration and inflammation, most of which were restored with either aspirin, metformin, resveratrol, or AD-01 (p < 0.05). Our 2D in vitro models recapitulate the response of the first trimester trophoblast cells to preeclampsia-like stresses, modelling inappropriate placental development, and demonstrate therapeutic potential of repurposed treatments.

Description:Objective: Advances in DNA sequencing and analysis of the respiratory microbiome highlight its close association with bronchiectasis phenotypes, revealing fresh opportunities for diagnosis, stratification, and personalized clinical intervention. An under-recognized condition, bronchiectasis is increasingly the subject of recent large-scale, multicentre, and longitudinal clinical studies including detailed analysis of the microbiome. In this review, we summarize recent progress in our understanding of the bronchiectasis microbiome within the context of its potential use in treatment decisions. Results: Diverse microbiome profiles exist in bronchiectasis, in line with the established disease heterogeneity including treatment response. Classical microbiology has established Pseudomonas aeruginosa and Haemophilus influenza as two microbial markers of disease, while holistic microbiome analysis has uncovered important associations with less common bacterial taxa including commensal an/or pathobiont species, including the emerging role of the fungal mycobiome, virome, and interactome. Integration of airway microbiomes with other high-dimensional biological and clinical datasets holds significant promise to determining treatable traits and mechanisms of disease related to the microbiome. Conclusions: The bronchiectasis microbiome is an emerging and key area of study with significant implications for understanding bronchiectasis, influencing treatment decisions and ultimately improving patient outcomes.

Description:Next-generation vaccines are essential to address the evolving nature of SARS-CoV-2 and to protect against emerging pandemic threats from other coronaviruses. These vaccines should elicit broad protection, provide long-lasting immunity and ensure equitable access for all populations. In this study, we developed a panel of chimeric, full-length spike antigens incorporating mutations from previous, circulating and predicted SARS-CoV-2 variants. The lead candidate (CoVEXS5) was produced through a high-yield production process in stable CHO cells achieving >95% purity, demonstrated long-term stability and elicited broadly cross-reactive neutralising antibodies when delivered to mice in a squalene emulsion adjuvant (Sepivac SWE™). In both mice and hamsters, CoVEXS5 immunisation reduced clinical disease signs, lung inflammation and organ viral titres after SARS-CoV-2 infection, including following challenge with the highly immunoevasive Omicron XBB.1.5 subvariant. In mice previously primed with a licenced mRNA vaccine (Comirnaty XBB.1.5, termed mRNA-XBB), CoVEXS5 boosting significantly increased neutralising antibody (nAb) levels against viruses from three sarbecoviruses clades. Boosting with CoVEXS5 via systemic delivery elicited CD4+ lung-resident memory T cells, typically associated with mucosal immunisation strategies, which were not detected following mRNA-XBB boosting. Vaccination of hamsters with CoVEXS5 conferred significant protection against weight loss after SARS-CoV-1 challenge, compared to mRNA-XBB immunisation, that correlated with anti-SARS-CoV-1 nAbs in the sera of vaccinated animals. These findings highlight the potential of a chimeric spike antigen, formulated in an open-access adjuvant, as a next-generation vaccine candidate to enhance cross-protection against emerging sarbecoviruses in vaccinated populations globally.

Description:Females are disproportionately affected by asthma. An increased understanding of how female sex hormones influence key pathophysiological processes that underpin asthma may identify new, more effective asthma therapies, particularly for females with severe, poorly controlled asthma. We assessed the effects of oral ethinylestradiol/levonorgestrel (representing OCP use) and depot-medroxyprogesterone acetate (DMPA) and estradiol injections on key features of experimental asthma, and determined their effects on glucose transporter-1 (GLUT-1). The effects of OCP use on clinical asthma outcomes, and the relationships between estrogen receptors and type 2 (T2), non-T2, and GLUT-1 responses, in clinical asthma were also determined. OCP and DMPA reduce T2 responses, disease features, and lung expression of GLUT-1, whereas estradiol increases lung expression of GLUT-1, and results in severe, corticosteroid-insensitive, neutrophil-enriched disease, in experimental asthma. OCP use is associated with reduced T2 cytokine and GLUT-1 responses in clinical asthma. GLUT-1 expression is increased in sputum of severe asthmatics, and positively correlates with estrogen receptor expression and both T2 and non-T2 inflammatory responses. Significantly, OCP or GLUT-1 inhibition protects against obesity-associated or estradiol-induced, severe, experimental asthma, respectively. Together, these data show how female sex hormones and the OCP likely modulate asthma severity by modifying GLUT-1 responses in the airways.