Publications
54 results found
Swieboda D, Thwaites R, Rice T, et al., 2024, Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth, Clinical and Experimental Immunology, Vol: 215, Pages: 1-14, ISSN: 0009-9104
Early life is a time of increased susceptibility to infectious diseases and development of allergy. Innate lymphocytes are crucial components of the initiation and regulation of immune responses at mucosal surfaces, but functional differences in innate lymphocytes early in life are not fully described. We aimed to characterise the abundance and function of different innate lymphocyte cell populations in cord blood in comparison to that of adults. Blood was collected from adult donors and umbilical vessels at birth. Multicolour flow cytometry panels were used to identify and characterise lymphocyte populations and their capacity to produce hallmark cytokines. Lymphocytes were more abundant in cord blood compared to adults, however, mucosal-associated invariant T (MAIT) cells and Natural Killer T (NKT)-like cells, were far less abundant. The capacity of NKT-like cells to produce cytokines and their expression of the cytotoxic granule protein granzyme B and the marker of terminal differentiation CD57 were much lower in cord blood than in adults. In contrast, Natural Killer (NK) cells were as abundant in cord blood as in adults, they could produce IFNγ, and their expression of granzyme B was not significantly different to that of adult NK cells, although CD57 expression was lower. All innate lymphoid cell (ILC) subsets were more abundant in cord blood, and ILC1 and ILC2 were capable of production of IFNγ and IL-13, respectively. In conclusion, different innate lymphoid cells differ in both abundance and function in peripheral blood at birth and with important implications for immunity in early life.
Goss C, Culley F, Parthasarathy P, et al., 2023, New Teaching and Assessment Practices in an Undergraduate Medicine Intercalated BSc in Endocrinology, Endocrine Abstracts
Jacobsen H, Walendy-Gnirss K, Tekin-Bubenheim N, et al., 2023, Offspring born to influenza A virus infected pregnant mice show increased vulnerability to viral and bacterial infections in early life, 12th International Workshop Reunion Island Reproductive Immunology, Immunological tolerance and Immunology of preeclampsia, Publisher: ELSEVIER IRELAND LTD, Pages: 7-8, ISSN: 0165-0378
Kim SY, Chen Q, Tseng P, et al., 2023, The pro-repair effects of tissue-derived extracellular vesicles are modified with ageing, Publisher: MARY ANN LIEBERT, INC, ISSN: 1937-3341
Goss C, Culley FJ, Parthasarathy P, et al., 2022, A paragigm shift in assessment of scientific skills in undergraduate medical education, Advances in Medical Education and Practice, Vol: 13, Pages: 123-127, ISSN: 1179-7258
The General Medical Council’s publication ‘Outcomes for Graduates’ places emphasis on doctors being able to integrate biomedical science, research and scholarship with clinical practice. In response, a new paradigm of assessment was introduced for the intercalated Bachelor of Science program at Imperial College School of Medicine in 2019. This innovative approach involves authentic “active learning” assessments analogous to tasks encountered in a research environment and intends to test a wider range of applied scientific skills than traditional examinations. Written assessments include a “Letter to the Editor”, scientific abstract, and production of a lay summary. A clinical case study titled “Science in Context” presents a real or virtual patient, with evaluation of current and emerging evidence within that field. Another assessment emulates the academic publishing process: groups submit a literature review and engage in reciprocal peer review of another group’s work. A rebuttal letter accompanies the final submission, detailing how feedback was addressed. Scientific presentation skills are developed through tasks including a research proposal pitch, discussion of therapies or diagnostics, or review of a paper. A data management assignment develops skills in hypothesis generation, performing analysis, and drawing conclusions. Finally, students conduct an original research project which is assessed via a written report in the format of a research paper and an oral presentation involving critical analysis of their project. We aspire to train clinicians who apply scientific principles to critique the evidence base of medical practice and possess the skillset to conduct high-quality research underpinned by the principles of best clinical and academic practice. Assessment drives learning, and active learning has been demonstrated to enhance academic performance and reduce attainment gaps in science education.
Jacobsen H, Walendy-Gnirss K, Tekin-Bubenheim N, et al., 2021, Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life, Nature Communications, Vol: 12, ISSN: 2041-1723
Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring.
Nicieza CD, Culley FJ, 2021, Age-associated changes to innate immune responses of resident lung cells, Publisher: WILEY, Pages: 273-273, ISSN: 0014-2980
Swieboda D, Guo Y, Sagawe S, et al., 2019, OMIP-062: A 14-Color, 16-antibody panel for immunophenotyping human innate yymphoid, myeloid and T cells in small volumes of whole blood and pediatric airway samples, Cytometry Part A, Vol: 95, Pages: 1231-1235, ISSN: 1552-4949
This 14‐color, 16‐antibody OMIP was designed for enumeration of leukocyte responses in pediatric samples, where sample volumes and cell numbers can be very low. Leukocytes identified by this panel include all major members of the innate lymphoid cell (ILC) family (ILC1s, ILC2s, and ILC3s), natural killer cells (NK cells), granulocytes (neutrophils and eosinophils), T‐cells (CD4+ and CD8+), mucosal‐associated invariant T cells (MAIT cells) and NKT‐like cells. The protocol was optimized using small volumes of peripheral blood and validated in airway samples obtained from children (< 2 years of age) admitted to a pediatric intensive care unit (PICU). Given this backdrop, this OMIP is widely applicable to clinical research using low volume or paucicellular samples, such as studies of innate and adaptive immune responses in infants and children, with potential clinical application in diagnostics and monitoring of patients by pediatricians.
Swieboda D, Thwaites R, Nadel S, et al., 2018, The role of innate lymphoid cells in early life lung infection, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
lambert L, Culley FJ, 2017, Innate Immunity to Respiratory Infection in Early Life, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Early life is a period of particular susceptibility to respiratory infections and symptoms are frequently more severe in infants than in adults. The neonatal immune system is generally held to be deficient in most compartments; responses to innate stimuli are weak, antigen-presenting cells have poor immunostimulatory activity and adaptive lymphocyte responses are limited, leading to poor immune memory and ineffective vaccine responses. For mucosal surfaces such as the lung, which is continuously exposed to airborne antigen and to potential pathogenic invasion, the ability to discriminate between harmless and potentially dangerous antigens is essential, to prevent inflammation that could lead to loss of gaseous exchange and damage to the developing lung tissue. We have only recently begun to define the differences in respiratory immunity in early life and its environmental and developmental influences. The innate immune system may be of relatively greater importance than the adaptive immune system in the neonatal and infant period than later in life, as it does not require specific antigenic experience. A better understanding of what constitutes protective innate immunity in the respiratory tract in this age group and the factors that influence its development should allow us to predict why certain infants are vulnerable to severe respiratory infections, design treatments to accelerate the development of protective immunity, and design age specific adjuvants to better boost immunity to infection in the lung.
Heath PT, Culley FJ, Jones CE, et al., 2017, Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis, Lancet Infectious Diseases, Vol: 17, Pages: e223-e234, ISSN: 1473-3099
Group B streptococcus and respiratory syncytial virus are leading causes of infant morbidity and mortality worldwide. No licensed vaccines are available for either disease, but vaccines for both are under development. Severe respiratory syncytial virus disease can be prevented by passively administered antibody. The presence of maternal IgG antibody specific to respiratory syncytial virus is associated with reduced prevalence and severity of respiratory syncytial virus disease in the first few weeks of life, whereas maternal serotype-specific anticapsular antibody is associated with protection against both early-onset and late-onset group B streptococcus disease. Therefore, vaccination in pregnancy might protect infants against both diseases. This report describes what is known about immune protection against group B streptococcus and respiratory syncytial virus, identifies knowledge gaps regarding the immunobiology of both diseases, and aims to prioritise research directions in maternal immunisation.
Openshaw PJM, Chiu C, Culley FJ, et al., 2017, Protective and Harmful Immunity to RSV Infection, Annual Review of Immunology, Vol: 35, Pages: 501-532, ISSN: 0732-0582
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
Makris S, Bajorek M, Culley F, et al., 2016, Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons, Journal of Innate Immunity, Vol: 8, ISSN: 1662-8128
Goritzka M, Makris S, Kausar F, et al., 2015, Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes, Journal of Experimental Medicine, Vol: 212, Pages: 699-714, ISSN: 0022-1007
Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)–coupled retinoic acid–inducible gene 1 (RIG-I)–like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN–dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN–mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.
Culley FJ, Darby M, Vira A, et al., 2015, The M3 muscarinic receptor Is required for optimal adaptive immunity to Helminth and bacterial infection, Plos Pathogens, Vol: 11, ISSN: 1553-7374
Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection.
Goritzka M, Durant L, Pereira C, et al., 2014, Alveolar macrophage-derived type I IFNs orchestrate immune responses to RSV through recruitment of antiviral monocytes, IMMUNOLOGY, Vol: 143, Pages: 104-104, ISSN: 0019-2805
Lambert L, Culley FJ, 2014, Hypo-responsive innate immunity in the neonatal lung, IMMUNOLOGY, Vol: 143, Pages: 109-109, ISSN: 0019-2805
Sabroe I, Dockrell DH, Culley FJ, 2014, RSV: a new box of delights for an old enemy, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 96, Pages: 945-947, ISSN: 0741-5400
Goritzka M, Makris S, Kausar F, et al., 2014, Alveolar macrophages modulate innate immune responses to Respiratory Syncytial Virus (RSV) infection through MAVS signalling and type I interferons, 9th European-Mucosal-Immunology-Group Meeting, Publisher: WILEY-BLACKWELL, Pages: 7-8, ISSN: 0019-2805
Lambert L, Sagfors AM, Openshaw PJM, et al., 2014, Immunity to RSV in early-life, FRONTIERS IN IMMUNOLOGY, Vol: 5, ISSN: 1664-3224
- Author Web Link
- Open Access Link
- Cite
- Citations: 132
Satkunanathan S, Kumar N, Bajorek M, et al., 2014, Respiratory Syncytial Virus Infection, TLR3 Ligands, and Proinflammatory Cytokines Induce CD161 Ligand LLT1 Expression on the Respiratory Epithelium, JOURNAL OF VIROLOGY, Vol: 88, Pages: 2366-2373, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 30
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed sequelae of neonatal RSV infection are dependent on cells of the innate immune system, Journal of Virology, ISSN: 0022-538X
Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are re-infected with the same virus as adults. Both T cells and host MHC genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult re-infection. Compared to those undergoing primary adult infection, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), interferon alpha (IFNα), CXCL1 (KC) and tumor necrosis factor alpha (TNFα) at 12-24h, and IL-4, IL-5, IFNγ and CCL11 (eotaxin) at day 4 after re-infection. Weight loss during re-infection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK depletion during re-infection attenuated weight loss, but did not alter T cell responses. Depleting alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection.
Farhadi N, Lambert L, Triulzi C, et al., 2013, Natural Killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation, Journal of Allergy and Clinical Immunology
BackgroundThe diverse roles of innate immune cells in the pathogenesis of asthma remain to be fully defined. Natural killer (NK) cells are innate lymphocytes which can regulate adaptive immune responses. NK cells are activated in asthma; however, their role in allergic airway inflammation is not fully understood.ObjectiveWe investigated the importance of NK cells in house dust mite (HDM) triggered allergic pulmonary inflammation. Specifically, we aimed to determine the role of the major NK cell activating receptor NKG2D and NK cell effector functions mediated by granzyme B.MethodsAllergic airway inflammation was induced in the airways of mice by repeated intranasal HDM extract administration and responses in wild type and NKG2D deficient mice were compared. Adoptive transfer studies were used to identify the cells and mechanisms involved.ResultsMice lacking NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway Th2 cells and no rise in serum IgE after multiple HDM allergen exposures. However, NKG2D was not required for pulmonary inflammation after a single inoculation of allergen. NKG2D deficient mice showed no alteration in responses to respiratory virus infection. Transfer of wild type NK cells (but not CD3+ cells) into NKG2D deficient mice restored allergic inflammatory responses only if the NK cells expressed granzyme B. ConclusionThese studies establish a pivotal role for NK cell NKG2D and granzyme B in the pathogenesis of HDM induced allergic lung disease, and identify novel therapeutic targets for the prevention and treatment of asthma.
Lambert L, Farhadi N, Culley FJ, 2013, The long-term effect of neonatal respiratory syncytial virus (RSV) infection on the response to adult allergen challenge, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 104-105, ISSN: 0019-2805
Lambert L, Farhadi N, Culley F, 2013, LSC 2013 abstract - The long-term effect of neonatal respiratory syncytial virus (RSV) infection on the response to adult allergen challenge, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Farhadi N, Guerra N, Openshaw PJ, et al., 2013, The Role Of Nk Cells In Allergic Inflammation Of The Lung, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Yamaguchi Y, Harker JA, Wang B, et al., 2012, Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection, JOURNAL OF VIROLOGY, Vol: 86, Pages: 10456-10461, ISSN: 0022-538X
- Author Web Link
- Open Access Link
- Cite
- Citations: 27
Loebbermann J, Thornton H, Durant L, et al., 2012, Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection, MUCOSAL IMMUNOLOGY, Vol: 5, Pages: 161-172, ISSN: 1933-0219
- Author Web Link
- Open Access Link
- Cite
- Citations: 136
Loebbermann J, Thornton H, Sparwasser T, et al., 2011, Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 181-181, ISSN: 0019-2805
Tregoning JS, Pribul PK, Pennycook AMJ, et al., 2010, The Chemokine MIP1α/CCL3 Determines Pathology in Primary RSV Infection by Regulating the Balance of T Cell Populations in the Murine Lung, PLOS ONE, Vol: 5, ISSN: 1932-6203
- Author Web Link
- Open Access Link
- Cite
- Citations: 38
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.