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Conference paperPalau H, Meng C, Bhargava A, et al., 2019,
Lentivirus Gene Therapy for Autoimmune Pulmonary Alveolar Proteinosis
, 22nd Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: CELL PRESS, Pages: 43-44, ISSN: 1525-0016 -
Journal articleAhmed B, Cox M, Cuthbertson L, et al., 2019,
Longitudinal development of the airway microbiota in infants with cystic fibrosis
, Scientific Reports, Vol: 9, ISSN: 2045-2322The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. We performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Quantitative PCR and Illumina sequencing of the 16S rRNA bacterial gene were performed. Data analyses were conducted in QIIME and Phyloseq in R. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.
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Journal articleDunning J, Blankley S, Hoang LT, et al., 2019,
Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza.
, Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
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Journal articleMelo J, Tunstall T, Pizzichini M, et al., 2019,
IL-5 levels in nasosorption and sputosorption correlate with sputum eosinophilia in allergic asthma
, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 240-243, ISSN: 1073-449X -
Journal articleSpadaro S, Park M, Turrini C, et al., 2019,
Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine
, Journal of Inflammation, Vol: 16, ISSN: 1476-9255Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for “lumping and splitting” are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939).Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-re
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Book chapterDavies G, Griesenbach U, Alton E, et al., 2019,
53 - Molecular Therapies for Cystic Fibrosis
, Kendig's Disorders of the Respiratory Tract in Children, Pages: 800-811.e3This chapter describes the therapeutic strategies for cystic fibrosis which are based on targeting cystic fibrosis transmembrane conductance regulator (CFTR), either at the gene or protein level. We provide updates on small molecule CFTR modulators and gene therapy, focusing on clinical development and evaluation. The field has seen significant progress over recent years, particularly with the CFTR potentiator, ivacaftor, in patients with class III mutations. Increased understanding of the abnormalities in the structure and function of CFTR protein will help optimize the approaches required for normalizing function and, in doing so, aid the rational design of clinical trials-both in terms of the development of more efficacious drugs and the selection of appropriate patient populations. While progress with gene therapy remains some way behind, potential benefits (including being mutation agnostic and a nonsystemic route of delivery) remain significant. It may be that future optimal approaches will harness the benefits of more than one of these approaches and lead to considerable synergy. The ultimate goal for molecular and advanced therapies in cystic fibrosis is to find drugs or combinations of drugs capable of restoring CFTR function, applicable to patients with any genetic mutation.
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Journal articleNuriev R, Johansson C, 2019,
Chemokine regulation of inflammation during respiratory syncytial virus infection.
, F1000Res, Vol: 8Respiratory syncytial virus (RSV) can cause severe lower respiratory tract infections especially in infants, immunocompromised individuals and the elderly and is the most common cause of infant hospitalisation in the developed world. The immune responses against RSV are crucial for viral control and clearance but, if dysregulated, can also result in immunopathology and impaired gas exchange. Lung immunity to RSV and other respiratory viruses begins with the recruitment of immune cells from the bloodstream into the lungs. This inflammatory process is controlled largely by chemokines, which are small proteins that are produced in response to innate immune detection of the virus or the infection process. These chemokines serve as chemoattractants for granulocytes, monocytes, lymphocytes and other leukocytes. In this review, we highlight recent advances in the field of RSV infection and disease, focusing on how chemokines regulate virus-induced inflammation.
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Journal articlePissaridou P, Allsopp LP, Wettstadt S, et al., 2018,
The Pseudomonas aeruginosa T6SS-VgrG1b spike is topped by a PAAR protein eliciting DNA damage to bacterial competitors
, Proceedings of the National Academy of Sciences of the United States of America, Vol: 115, Pages: 12519-12524, ISSN: 0027-8424The type VI secretion system (T6SS) is a supramolecular complex involved in the delivery of potent toxins during bacterial competition. Pseudomonas aeruginosa possesses three T6SS gene clusters and several hcp and vgrG gene islands, the latter encoding the spike at the T6SS tip. The vgrG1b cluster encompasses seven genes whose organization and sequences are highly conserved in P. aeruginosa genomes, except for two genes that we called tse7 and tsi7. We show that Tse7 is a Tox-GHH2 domain nuclease which is distinct from other T6SS nucleases identified thus far. Expression of this toxin induces the SOS response, causes growth arrest and ultimately results in DNA degradation. The cytotoxic domain of Tse7 lies at its C terminus, while the N terminus is a predicted PAAR domain. We find that Tse7 sits on the tip of the VgrG1b spike and that specific residues at the PAAR–VgrG1b interface are essential for VgrG1b-dependent delivery of Tse7 into bacterial prey. We also show that the delivery of Tse7 is dependent on the H1-T6SS cluster, and injection of the nuclease into bacterial competitors is deployed for interbacterial competition. Tsi7, the cognate immunity protein, protects the producer from the deleterious effect of Tse7 through a direct protein–protein interaction so specific that toxin/immunity pairs are effective only if they originate from the same P. aeruginosa isolate. Overall, our study highlights the diversity of T6SS effectors, the exquisite fitting of toxins on the tip of the T6SS, and the specificity in Tsi7-dependent protection, suggesting a role in interstrain competition.
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Conference paperSimmonds NJ, Pabary R, Kohlhaufl J, et al., 2018,
THE ADDED VALUE OF NASAL POTENTIAL DIFFERENCE MEASUREMENT WHEN FIRST-LINE CYSTIC FIBROSIS (CF) INVESTIGATIONS ARE NON-DIAGNOSTIC
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A85, ISSN: 0040-6376 -
Conference paperLund-Palau H, Meng C, Pilou A, et al., 2018,
LENTIVIRUS GM-CSF GENE THERAPY AMELIORATES AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS
, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A2, ISSN: 0040-6376
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