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Prof. Neil Mabbott
The Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK

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Research Keywords & Expertise

0 Aging
0 Neuroimmunology
0 Pathogenesis
0 Prion diseases/transmissible spongiform encephalopathies
0 Host-pathogen interactions in the mucosal immune system

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Pathogenesis
Aging
Host-pathogen interactions in the mucosal immune system
Prion diseases/transmissible spongiform encephalopathies

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Accepted manuscript
Published: 17 August 2021 in Immunotherapy Advances
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We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been created and received either emergency approval or full licensure. To attain the upper hand, maximum vaccine synthesis, deployment and uptake as rapidly as possible is essential. However, vaccine uptake, particularly in younger adults is dropping, at least in part fuelled by reports of rare complications associated with specific vaccines. This review considers how vaccination with adenovirus vector-based vaccines against the SARS-CoV-2 coronavirus might cause rare cases of thrombosis and thrombocytopenia in some recipients. A thorough understanding of the underlying cellular and molecular mechanisms that mediate this syndrome may help to identify methods to prevent these very rare, but serious side-effects. This will also help facilitate the identification of those at highest risk from these outcomes, so that we can work towards a stratified approach to vaccine deployment to mitigate these risks.

ACS Style

Eleanor R Gaunt; Neil A Mabbott. The clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunization with adenovirus vector-based SARS-CoV-2 vaccines. Immunotherapy Advances 2021, 1 .

AMA Style

Eleanor R Gaunt, Neil A Mabbott. The clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunization with adenovirus vector-based SARS-CoV-2 vaccines. Immunotherapy Advances. 2021; ():1.

Chicago/Turabian Style

Eleanor R Gaunt; Neil A Mabbott. 2021. "The clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunization with adenovirus vector-based SARS-CoV-2 vaccines." Immunotherapy Advances , no. : 1.

Article
Published: 11 August 2021
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Microglia play key roles in brain homeostasis as well as responses to neurodegeneration and neuroinflammatory processes caused by physical disease and psychosocial stress. The pig is a physiologically-relevant model species for studying human neurological disorders, many of which are associated with microglial dysfunction. Furthermore, pigs are an important agricultural species, and there is a need to understand how microglial function affects their welfare. As a basis for improved understanding to enhance biomedical and agricultural research, we sought to characterise pig microglial identity at genome-wide scale and conduct inter-species comparisons. We isolated pig hippocampal tissue and microglia from frontal cortex, hippocampus and cerebellum, as well as alveolar macrophages from the lungs and conducted RNA-sequencing (RNAseq). By comparing the transcriptomic profiles between microglia, macrophages, and hippocampal tissue, we derived a set of 365 highly-enriched genes defining the porcine core microglial signature. We found brain regional heterogeneity based on 215 genes showing significant (adjusted p<0.01) regional variations and that cerebellar microglia were most distinct. We compared normalized gene expression for microglia from human, mice and pigs using microglia signature gene lists derived from each species and demonstrated that a core microglial marker gene signature is conserved across species, but that species-specific expression subsets also exist. Importantly, pig and human microglia shared greater similarity than pig and murine microglia. Our data provide a valuable resource defining the pig microglial transcriptome signature that highlights pigs as a useful large animal species bridging between rodents and humans in which to study the role of microglia during homeostasis and disease. Main Points - Defined a pig microglial transcriptome signature comprising 365 genes. - Demonstrated regional variance in the pig microglial transcriptome across the brain. - Revealed greater similarity between pig and human microglia than mouse.

ACS Style

Barbara B Shih; Sarah M Brown; Lucas Lefevre; Neil A Mabbott; Josef Priller; Gerard Thompson; Alistair B Lawrence; Barry W McColl. Defining the pig microglial transcriptome reveals their core signature, regional heterogeneity, and similarity with humans. 2021, 1 .

AMA Style

Barbara B Shih, Sarah M Brown, Lucas Lefevre, Neil A Mabbott, Josef Priller, Gerard Thompson, Alistair B Lawrence, Barry W McColl. Defining the pig microglial transcriptome reveals their core signature, regional heterogeneity, and similarity with humans. . 2021; ():1.

Chicago/Turabian Style

Barbara B Shih; Sarah M Brown; Lucas Lefevre; Neil A Mabbott; Josef Priller; Gerard Thompson; Alistair B Lawrence; Barry W McColl. 2021. "Defining the pig microglial transcriptome reveals their core signature, regional heterogeneity, and similarity with humans." , no. : 1.

Journal article
Published: 10 May 2021 in Scientific Reports
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Infections with Trypanosoma brucei sp. are established after the injection of metacyclic trypomastigotes into the skin dermis by the tsetse fly vector. The parasites then gain access to the local lymphatic vessels to infect the local draining lymph nodes and disseminate systemically via the bloodstream. Macrophages are considered to play an important role in host protection during the early stage of systemic trypanosome infections. Macrophages are abundant in the skin dermis, but relatively little is known of their impact on susceptibility to intradermal (ID) trypanosome infections. We show that although dermal injection of colony stimulating factor 1 (CSF1) increased the local abundance of macrophages in the skin, this did not affect susceptibility to ID T. brucei infection. However, bacterial LPS-stimulation in the dermis prior to ID trypanosome infection significantly reduced disease susceptibility. In vitro assays showed that LPS-stimulated macrophage-like RAW264.7 cells had enhanced cytotoxicity towards T. brucei, implying that dermal LPS-treatment may similarly enhance the ability of dermal macrophages to eliminate ID injected T. brucei parasites in the skin. A thorough understanding of the factors that reduce susceptibility to ID injected T. brucei infections may lead to the development of novel strategies to help reduce the transmission of African trypanosomes.

ACS Style

Omar A. Alfituri; Enock M. Mararo; Pieter C. Steketee; Liam J. Morrison; Neil A. Mabbott. Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection. Scientific Reports 2021, 11, 1 -10.

AMA Style

Omar A. Alfituri, Enock M. Mararo, Pieter C. Steketee, Liam J. Morrison, Neil A. Mabbott. Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection. Scientific Reports. 2021; 11 (1):1-10.

Chicago/Turabian Style

Omar A. Alfituri; Enock M. Mararo; Pieter C. Steketee; Liam J. Morrison; Neil A. Mabbott. 2021. "Dermal bacterial LPS-stimulation reduces susceptibility to intradermal Trypanosoma brucei infection." Scientific Reports 11, no. 1: 1-10.

Journal article
Published: 19 March 2021 in Communications Biology
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Mammalian three-dimensional (3D) enteroids mirror in vivo intestinal organisation and are powerful tools to investigate intestinal cell biology and host–pathogen interactions. We have developed complex multilobulated 3D chicken enteroids from intestinal embryonic villi and adult crypts. These avian enteroids develop optimally in suspension without the structural support required to produce mammalian enteroids, resulting in an inside-out enteroid conformation with media-facing apical brush borders. Histological and transcriptional analyses show these enteroids comprise of differentiated intestinal epithelial cells bound by cell-cell junctions, and notably, include intraepithelial leukocytes and an inner core of lamina propria leukocytes. The advantageous polarisation of these enteroids has enabled infection of the epithelial apical surface withSalmonellaTyphimurium, influenza A virus andEimeria tenellawithout the need for micro-injection. We have created a comprehensive model of the chicken intestine which has the potential to explore epithelial and leukocyte interactions and responses in host–pathogen, food science and pharmaceutical research.

ACS Style

Tessa J. Nash; Katrina M. Morris; Neil A. Mabbott; Lonneke Vervelde. Inside-out chicken enteroids with leukocyte component as a model to study host–pathogen interactions. Communications Biology 2021, 4, 1 -15.

AMA Style

Tessa J. Nash, Katrina M. Morris, Neil A. Mabbott, Lonneke Vervelde. Inside-out chicken enteroids with leukocyte component as a model to study host–pathogen interactions. Communications Biology. 2021; 4 (1):1-15.

Chicago/Turabian Style

Tessa J. Nash; Katrina M. Morris; Neil A. Mabbott; Lonneke Vervelde. 2021. "Inside-out chicken enteroids with leukocyte component as a model to study host–pathogen interactions." Communications Biology 4, no. 1: 1-15.

Journal article
Published: 14 January 2021 in Nature Aging
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ACS Style

Emma S. Chambers; Milica Vukmanovic-Stejic; Barbara B. Shih; Hugh Trahair; Priya Subramanian; Oliver P. Devine; James Glanville; Derek Gilroy; Malcolm H. A. Rustin; Tom C. Freeman; Neil A. Mabbott; Arne N. Akbar. Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nature Aging 2021, 1, 101 -113.

AMA Style

Emma S. Chambers, Milica Vukmanovic-Stejic, Barbara B. Shih, Hugh Trahair, Priya Subramanian, Oliver P. Devine, James Glanville, Derek Gilroy, Malcolm H. A. Rustin, Tom C. Freeman, Neil A. Mabbott, Arne N. Akbar. Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nature Aging. 2021; 1 (1):101-113.

Chicago/Turabian Style

Emma S. Chambers; Milica Vukmanovic-Stejic; Barbara B. Shih; Hugh Trahair; Priya Subramanian; Oliver P. Devine; James Glanville; Derek Gilroy; Malcolm H. A. Rustin; Tom C. Freeman; Neil A. Mabbott; Arne N. Akbar. 2021. "Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging." Nature Aging 1, no. 1: 101-113.

Preprint content
Published: 06 January 2021
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SUMMARY Prion diseases are transmissible, neurodegenerative disorders to which there are no cures. Previous studies show that reduction of microglia accelerates prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. InCsf1r ΔFIREmice, the deletion of an enhancer withinCsf1rspecifically blocks microglia development, however, their brains develop normally with none of the deficits reported in other microglia-deficient models.Csf1r ΔFIREmice were used as a refined model to study the impact of microglia-deficiency on CNS prion disease. AlthoughCsf1r ΔFIREmice succumbed to prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. Our data suggest that rather than engulfing and degrading prions, the microglia instead provide neuroprotection and restrict the harmful activities of reactive astrocytes.

ACS Style

Barry M. Bradford; Lynne I. McGuire; David A. Hume; Clare Pridans; Neil A. Mabbott. Complete microglia deficiency accelerates prion disease without enhancing CNS prion accumulation. 2021, 1 .

AMA Style

Barry M. Bradford, Lynne I. McGuire, David A. Hume, Clare Pridans, Neil A. Mabbott. Complete microglia deficiency accelerates prion disease without enhancing CNS prion accumulation. . 2021; ():1.

Chicago/Turabian Style

Barry M. Bradford; Lynne I. McGuire; David A. Hume; Clare Pridans; Neil A. Mabbott. 2021. "Complete microglia deficiency accelerates prion disease without enhancing CNS prion accumulation." , no. : 1.

Review
Published: 02 October 2020 in International Journal of Molecular Sciences
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Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

ACS Style

Neil A. Mabbott; Barry M. Bradford; Reiss Pal; Rachel Young; David S. Donaldson. The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis. International Journal of Molecular Sciences 2020, 21, 7299 .

AMA Style

Neil A. Mabbott, Barry M. Bradford, Reiss Pal, Rachel Young, David S. Donaldson. The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis. International Journal of Molecular Sciences. 2020; 21 (19):7299.

Chicago/Turabian Style

Neil A. Mabbott; Barry M. Bradford; Reiss Pal; Rachel Young; David S. Donaldson. 2020. "The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis." International Journal of Molecular Sciences 21, no. 19: 7299.

Journal article
Published: 01 June 2020 in iScience
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Aging has a profound effect on the immune system, termed immunosenescence, resulting in increased incidence and severity of infections and decreased efficacy of vaccinations. We previously showed that immunosurveillance in the intestine, achieved primarily through antigen sampling M cells in the follicle associated epithelium (FAE) of Peyer's patches, was compromised during aging due to a decline in M cell functional maturation. The intestinal microbiota also changes significantly with age, but whether this affects M cell maturation was not known. We show that housing of aged mice on used bedding from young mice, or treatment with bacterial flagellin, were each sufficient to enhance the functional maturation of M cells in Peyer's patches. An understanding of the mechanisms underlying the influence of the intestinal microbiota on M cells has the potential to lead to new methods to enhance the efficacy of oral vaccination in aged individuals.

ACS Style

David S. Donaldson; Jolinda Pollock; Prerna Vohra; Mark P. Stevens; Neil A. Mabbott. Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice. iScience 2020, 23, 101147 .

AMA Style

David S. Donaldson, Jolinda Pollock, Prerna Vohra, Mark P. Stevens, Neil A. Mabbott. Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice. iScience. 2020; 23 (6):101147.

Chicago/Turabian Style

David S. Donaldson; Jolinda Pollock; Prerna Vohra; Mark P. Stevens; Neil A. Mabbott. 2020. "Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice." iScience 23, no. 6: 101147.

Preprint content
Published: 03 April 2020
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Ageing results in a decline in immune function. We showed previously that healthy older humans (>65 years old) have reduced antigen-specific cutaneous immunity to varicella zoster virus (VZV) antigen challenge. This was associated with p38 MAP kinase driven inflammation that was induced by mild tissue injury caused by the injection of the antigen itself. Here we show that non-specific injury induced by injection of air or saline into the skin of older adults recruits CCR2+CD14+ monocytes by CCL2 produced by senescent fibroblasts. These monocytes reduced TRM proliferation via secretion of prostaglandin E2 (PGE2). Pre-treatment with a p38-MAPK inhibitor (Losmapimod) in older adults in vivo significantly decreased CCL2 expression, recruitment of monocyte into the skin, COX2 expression and PGE2 production. This enhanced the VZV response in the skin. Therefore, local inflammation arising from interaction between senescent cells and monocytes leads to immune decline in the skin during ageing, a process that can be reversed.SummaryInflammation resulting from tissue injury blocks antigen-specific cutaneous immunity during ageing. Monocytes recruited to the skin inhibit TRM function through COX2-derived prostaglandin E2 production. Blocking inflammation and resulting prostaglandin E2 production with a p38-MAP kinase inhibitor significantly enhances cutaneous antigen-specific responses.

ACS Style

Emma S Chambers; Milica Vukmanovic-Stejic; Barbara B Shih; Hugh Trahair; Priya Subramanian; Oliver P Devine; James Glanville; Derek Gilroy; Malcolm Rustin; Tom C Freeman; Neil A Mabbott; Arne N Akbar. Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing. 2020, 1 .

AMA Style

Emma S Chambers, Milica Vukmanovic-Stejic, Barbara B Shih, Hugh Trahair, Priya Subramanian, Oliver P Devine, James Glanville, Derek Gilroy, Malcolm Rustin, Tom C Freeman, Neil A Mabbott, Arne N Akbar. Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing. . 2020; ():1.

Chicago/Turabian Style

Emma S Chambers; Milica Vukmanovic-Stejic; Barbara B Shih; Hugh Trahair; Priya Subramanian; Oliver P Devine; James Glanville; Derek Gilroy; Malcolm Rustin; Tom C Freeman; Neil A Mabbott; Arne N Akbar. 2020. "Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing." , no. : 1.

Journal article
Published: 30 March 2020 in Nature Immunology
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Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27−CD28−CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27−CD28−CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27−CD28−CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.

ACS Style

Branca I. Pereira; Roel P. H. De Maeyer; Luciana P. Covre; Djamel Nehar-Belaid; Alessio Lanna; Sophie Ward; Radu Marches; Emma S. Chambers; Daniel C. O. Gomes; Natalie E. Riddell; Mala K. Maini; Vitor H. Teixeira; Samuel M. Janes; Derek W. Gilroy; Anis Larbi; Neil A. Mabbott; Duygu Ucar; George A. Kuchel; Sian M. Henson; Jessica Strid; Jun H. Lee; Jacques Banchereau; Arne N. Akbar. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nature Immunology 2020, 21, 684 -694.

AMA Style

Branca I. Pereira, Roel P. H. De Maeyer, Luciana P. Covre, Djamel Nehar-Belaid, Alessio Lanna, Sophie Ward, Radu Marches, Emma S. Chambers, Daniel C. O. Gomes, Natalie E. Riddell, Mala K. Maini, Vitor H. Teixeira, Samuel M. Janes, Derek W. Gilroy, Anis Larbi, Neil A. Mabbott, Duygu Ucar, George A. Kuchel, Sian M. Henson, Jessica Strid, Jun H. Lee, Jacques Banchereau, Arne N. Akbar. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nature Immunology. 2020; 21 (6):684-694.

Chicago/Turabian Style

Branca I. Pereira; Roel P. H. De Maeyer; Luciana P. Covre; Djamel Nehar-Belaid; Alessio Lanna; Sophie Ward; Radu Marches; Emma S. Chambers; Daniel C. O. Gomes; Natalie E. Riddell; Mala K. Maini; Vitor H. Teixeira; Samuel M. Janes; Derek W. Gilroy; Anis Larbi; Neil A. Mabbott; Duygu Ucar; George A. Kuchel; Sian M. Henson; Jessica Strid; Jun H. Lee; Jacques Banchereau; Arne N. Akbar. 2020. "Sestrins induce natural killer function in senescent-like CD8+ T cells." Nature Immunology 21, no. 6: 684-694.

Journal article
Published: 12 March 2020 in Scientific Reports
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Prion infections in the central nervous system (CNS) can cause extensive neurodegeneration. Systemic inflammation can affect the progression of some neurodegenerative disorders. Therefore, we used the gastrointestinal helminth pathogen Trichuris muris to test the hypothesis that a chronic systemic inflammatory response to a gastrointestinal infection would similarly affect CNS prion disease pathogenesis. Mice were injected with prions directly into the CNS and subsequently orally co-infected with T. muris before the onset of clinical signs. We show that co-infection with a low dose of T. muris that leads to the development of a chronic T helper cell type 1-polarized systemic immune response accelerated the onset of clinical prion disease. In contrast, co-infection with a high dose of T. muris that induces a T helper cell type 2-polarized immune response did not affect prion disease pathogenesis. The reduced survival times in mice co-infected with a low dose of T. muris on d 105 after CNS prion infection coincided with enhanced astrocyte activation in the brain during the preclinical phase. These data aid our understanding of how systemic inflammation may augment the progression of neurodegeneration in the CNS.

ACS Style

David S. Donaldson; Barry M. Bradford; Kathryn J. Else; Neil A. Mabbott. Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase. Scientific Reports 2020, 10, 4554 -17.

AMA Style

David S. Donaldson, Barry M. Bradford, Kathryn J. Else, Neil A. Mabbott. Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase. Scientific Reports. 2020; 10 (1):4554-17.

Chicago/Turabian Style

David S. Donaldson; Barry M. Bradford; Kathryn J. Else; Neil A. Mabbott. 2020. "Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase." Scientific Reports 10, no. 1: 4554-17.

Preprint content
Published: 18 February 2020
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SUMMARYAgeing has a profound effect on the immune system, termed immunosenescence, resulting in increased incidence and severity of infections and decreased efficacy of vaccinations. We previously showed that immunosurveillance in the intestine, achieved primarily through antigen sampling M cells in the follicle associated epithelium (FAE) of Peyer’s patches, was compromised during ageing due to a decline in M cell functional maturation. The intestinal microbiota also changes significantly with age, but whether this affects M cell maturation was not known. We show that housing of aged mice on used bedding from young mice, or treatment with bacterial flagellin, were each sufficient to enhance the functional maturation of M cells in Peyer’s patches. An understanding of the mechanisms underlying the influence of the intestinal microbiota on M cells has the potential to lead to new methods to enhance the efficacy of oral vaccination in aged individuals.

ACS Style

David S. Donaldson; Jolinda Pollock; Prerna Vohra; Mark P. Stevens; Neil A. Mabbott. Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice. 2020, 1 .

AMA Style

David S. Donaldson, Jolinda Pollock, Prerna Vohra, Mark P. Stevens, Neil A. Mabbott. Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice. . 2020; ():1.

Chicago/Turabian Style

David S. Donaldson; Jolinda Pollock; Prerna Vohra; Mark P. Stevens; Neil A. Mabbott. 2020. "Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice." , no. : 1.

Journal article
Published: 13 December 2019 in Scientific Reports
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Prion diseases are a unique, infectious, neurodegenerative disorders that can affect animals and humans. Data from mouse transmissions show that efficient infection of the host after intravenous (IV) prion exposure is dependent upon the early accumulation and amplification of the prions on stromal follicular dendritic cells (FDC) in the B cell follicles. How infectious prions are initially conveyed from the blood-stream to the FDC in the spleen is uncertain. Addressing this issue is important as susceptibility to peripheral prion infections can be reduced by treatments that prevent the early accumulation of prions upon FDC. The marginal zone (MZ) in the spleen contains specialized subsets of B cells and macrophages that are positioned to continuously monitor the blood-stream and remove pathogens, toxins and apoptotic cells. The continual shuttling of MZ B cells between the MZ and the B-cell follicle enables them to efficiently capture and deliver blood-borne antigens and antigen-containing immune complexes to splenic FDC. We tested the hypothesis that MZ B cells also play a role in the initial shuttling of prions from the blood-stream to FDC. MZ B cells were temporarily depleted from the MZ by antibody-mediated blocking of integrin function. We show that depletion of MZ B cells around the time of IV prion exposure did not affect the early accumulation of blood-borne prions upon splenic FDC or reduce susceptibility to IV prion infection. In conclusion, our data suggest that the initial delivery of blood-borne prions to FDC in the spleen occurs independently of MZ B cells.

ACS Style

Barry M. Bradford; Neil A. Mabbott. Unaltered intravenous prion disease pathogenesis in the temporary absence of marginal zone B cells. Scientific Reports 2019, 9, 1 -9.

AMA Style

Barry M. Bradford, Neil A. Mabbott. Unaltered intravenous prion disease pathogenesis in the temporary absence of marginal zone B cells. Scientific Reports. 2019; 9 (1):1-9.

Chicago/Turabian Style

Barry M. Bradford; Neil A. Mabbott. 2019. "Unaltered intravenous prion disease pathogenesis in the temporary absence of marginal zone B cells." Scientific Reports 9, no. 1: 1-9.

Immunology
Published: 26 November 2019 in Frontiers in Immunology
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Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces

ACS Style

Neil A. Mabbott; Koji Hase. Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces. Frontiers in Immunology 2019, 10, 1 .

AMA Style

Neil A. Mabbott, Koji Hase. Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces. Frontiers in Immunology. 2019; 10 ():1.

Chicago/Turabian Style

Neil A. Mabbott; Koji Hase. 2019. "Editorial: Immunological Consequences of Antigen Sampling at Mucosal Surfaces." Frontiers in Immunology 10, no. : 1.

Research article
Published: 03 October 2019 in PLoS Pathogens
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Specific Escherichia coli isolates lysogenised with prophages that express Shiga toxin (Stx) can be a threat to human health, with cattle being an important natural reservoir. In many countries the most severe pathology is associated with enterohaemorrhagic E. coli (EHEC) serogroups that express Stx subtype 2a. In the United Kingdom, phage type (PT) 21/28 O157 strains have emerged as the predominant cause of life-threatening EHEC infections and this phage type commonly encodes both Stx2a and Stx2c toxin types. PT21/28 is also epidemiologically linked to super-shedding (>103 cfu/g of faeces) which is significant for inter-animal transmission and human infection as demonstrated using modelling studies. We demonstrate that Stx2a is the main toxin produced by stx2a+/stx2c+ PT21/28 strains induced with mitomycin C and this is associated with more rapid induction of gene expression from the Stx2a-encoding prophage compared to that from the Stx2c-encoding prophage. Bacterial supernatants containing either Stx2a and/or Stx2c were demonstrated to restrict growth of bovine gastrointestinal organoids with no restriction when toxin production was not induced or prevented by mutation. Isogenic strains that differed in their capacity to produce Stx2a were selected for experimental oral colonisation of calves to assess the significance of Stx2a for both super-shedding and transmission between animals. Restoration of Stx2a expression in a PT21/28 background significantly increased animal-to-animal transmission and the number of sentinel animals that became super-shedders. We propose that while both Stx2a and Stx2c can restrict regeneration of the epithelium, it is the relatively rapid and higher levels of Stx2a induction, compared to Stx2c, that have contributed to the successful emergence of Stx2a+ E. coli isolates in cattle in the last 40 years. We propose a model in which Stx2a enhances E. coli O157 colonisation of in-contact animals by restricting regeneration and turnover of the colonised gastrointestinal epithelium. Enterohaemorrhagic E. coli (EHEC) O157 strains are found in cattle where they are asymptomatic, while human exposure can lead to severe symptoms including bloody diarrhoea and kidney damage due to the activity of Shiga toxin (Stx). The most serious symptoms in humans are associated with isolates that encode Stx subtype 2a. The advantage of these toxins in the animal reservoir is still not clear, however there is experimental evidence implicating Stx with increased bacterial adherence, immune modulation and suppression of predatory protozoa. In this study, the hypothesis that Stx2a is important for super-shedding and calf-to-calf transmission was tested by comparing excretion and transmission dynamics of E. coli O157 strains with and without Stx2a. While Stx2a did not alter excretion levels when calfs were orally challenge, it enabled colonisation of more in contact ‘sentinel’ animals in our transmission model. We show that Stx2a is generally induced more rapidly than Stx2c, resulting in increased levels of Stx2a expression. Both Stx2a and Stx2c were able to restrict cellular proliferation of epithelial cells in cultured bovine enteroids. Taken together, we propose that rapid production of Stx2a and its role in establishing E. coli O157 colonisation in the bovine gastrointestinal tract facilitate effective transmission and have led to its expansion in the cattle E. coli O157 population.

ACS Style

Stephen Fitzgerald; Amy E. Beckett; Javier Palarea-Albaladejo; Sean McAteer; Sharif Shaaban; Jason Morgan; Nur Indah Ahmad; Rachel Young; Neil A. Mabbott; Liam Morrison; James L. Bono; David L. Gally; Tom N. McNeilly. Shiga toxin sub-type 2a increases the efficiency of Escherichia coli O157 transmission between animals and restricts epithelial regeneration in bovine enteroids. PLoS Pathogens 2019, 15, e1008003 .

AMA Style

Stephen Fitzgerald, Amy E. Beckett, Javier Palarea-Albaladejo, Sean McAteer, Sharif Shaaban, Jason Morgan, Nur Indah Ahmad, Rachel Young, Neil A. Mabbott, Liam Morrison, James L. Bono, David L. Gally, Tom N. McNeilly. Shiga toxin sub-type 2a increases the efficiency of Escherichia coli O157 transmission between animals and restricts epithelial regeneration in bovine enteroids. PLoS Pathogens. 2019; 15 (10):e1008003.

Chicago/Turabian Style

Stephen Fitzgerald; Amy E. Beckett; Javier Palarea-Albaladejo; Sean McAteer; Sharif Shaaban; Jason Morgan; Nur Indah Ahmad; Rachel Young; Neil A. Mabbott; Liam Morrison; James L. Bono; David L. Gally; Tom N. McNeilly. 2019. "Shiga toxin sub-type 2a increases the efficiency of Escherichia coli O157 transmission between animals and restricts epithelial regeneration in bovine enteroids." PLoS Pathogens 15, no. 10: e1008003.

Journal article
Published: 19 July 2019 in Nature Communications
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The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals. The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.

ACS Style

Rocío Rojo; Anna Raper; Derya D. Ozdemir; Lucas Lefevre; Kathleen Grabert; Evi Wollscheid-Lengeling; Barry Bradford; Melanie Caruso; Iveta Gazova; Alejandra Sánchez; Zofia M. Lisowski; Joana Alves; Irene Molina-Gonzalez; Hayk Davtyan; Rebecca J. Lodge; James D. Glover; Robert Wallace; David Munro; Eyal David; Ido Amit; Veronique Miron; Josef Priller; Stephen J. Jenkins; Giles E. Hardingham; Mathew Blurton-Jones; Neil A. Mabbott; Kim M. Summers; Peter Hohenstein; David A. Hume; Clare Pridans. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nature Communications 2019, 10, 1 -17.

AMA Style

Rocío Rojo, Anna Raper, Derya D. Ozdemir, Lucas Lefevre, Kathleen Grabert, Evi Wollscheid-Lengeling, Barry Bradford, Melanie Caruso, Iveta Gazova, Alejandra Sánchez, Zofia M. Lisowski, Joana Alves, Irene Molina-Gonzalez, Hayk Davtyan, Rebecca J. Lodge, James D. Glover, Robert Wallace, David Munro, Eyal David, Ido Amit, Veronique Miron, Josef Priller, Stephen J. Jenkins, Giles E. Hardingham, Mathew Blurton-Jones, Neil A. Mabbott, Kim M. Summers, Peter Hohenstein, David A. Hume, Clare Pridans. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nature Communications. 2019; 10 (1):1-17.

Chicago/Turabian Style

Rocío Rojo; Anna Raper; Derya D. Ozdemir; Lucas Lefevre; Kathleen Grabert; Evi Wollscheid-Lengeling; Barry Bradford; Melanie Caruso; Iveta Gazova; Alejandra Sánchez; Zofia M. Lisowski; Joana Alves; Irene Molina-Gonzalez; Hayk Davtyan; Rebecca J. Lodge; James D. Glover; Robert Wallace; David Munro; Eyal David; Ido Amit; Veronique Miron; Josef Priller; Stephen J. Jenkins; Giles E. Hardingham; Mathew Blurton-Jones; Neil A. Mabbott; Kim M. Summers; Peter Hohenstein; David A. Hume; Clare Pridans. 2019. "Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations." Nature Communications 10, no. 1: 1-17.

Journal article
Published: 03 June 2019 in Nature Communications
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The germinal center (GC) reaction in Peyer's patches (PP) requires continuous access to antigens, but how this is achieved is not known. Here we show that activated antigen-specific CCR6+CCR1+GL7- B cells make close contact with M cells in the subepithelial dome (SED). Using in situ photoactivation analysis of antigen-specific SED B cells, we find migration of cells towards the GC. Following antigen injection into ligated intestinal loops containing PPs, 40% of antigen-specific SED B cells bind antigen within 2 h, whereas unspecifc cells do not, indicating B cell-receptor involvment. Antigen-loading is not observed in M cell-deficient mice, but is unperturbed in mice depleted of classical dendritic cells (DC). Thus, we report a M cell-B cell antigen-specific transporting pathway in PP that is independent of DC. We propose that this antigen transporting pathway has a critical role in gut IgA responses, and should be taken into account when developing mucosal vaccines.

ACS Style

Rathan Joy Komban; Anneli Strömberg; Adi Biram; Jakob Cervin; Cristina Lebrero-Fernández; Neil Mabbott; Ulf Yrlid; Ziv Shulman; Mats Bemark; Nils Lycke. Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome. Nature Communications 2019, 10, 2423 .

AMA Style

Rathan Joy Komban, Anneli Strömberg, Adi Biram, Jakob Cervin, Cristina Lebrero-Fernández, Neil Mabbott, Ulf Yrlid, Ziv Shulman, Mats Bemark, Nils Lycke. Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome. Nature Communications. 2019; 10 (1):2423.

Chicago/Turabian Style

Rathan Joy Komban; Anneli Strömberg; Adi Biram; Jakob Cervin; Cristina Lebrero-Fernández; Neil Mabbott; Ulf Yrlid; Ziv Shulman; Mats Bemark; Nils Lycke. 2019. "Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome." Nature Communications 10, no. 1: 2423.

Journal article
Published: 30 April 2019 in Scientific Reports
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The early replication of some orally-acquired prion strains upon stromal-derived follicular dendritic cells (FDC) within the small intestinal Peyer's patches is essential to establish host infection, and for the disease to efficiently spread to the brain. Factors that influence the early accumulation of prions in Peyer's patches can directly influence disease pathogenesis. The host's immune response to a gastrointestinal helminth infection can alter susceptibility to co-infection with certain pathogenic bacteria and viruses. Here we used the natural mouse small intestine-restricted helminth pathogen Heligmosomoides polygyrus to test the hypothesis that pathology specifically within the small intestine caused by a helminth co-infection would influence oral prion disease pathogenesis. When mice were co-infected with prions on d 8 after H. polygyrus infection the early accumulation of prions within Peyer's patches was reduced and survival times significantly extended. Natural prion susceptible hosts such as sheep, deer and cattle are regularly exposed to gastrointestinal helminth parasites. Our data suggest that co-infections with small intestine-restricted helminth pathogens may be important factors that influence oral prion disease pathogenesis.

ACS Style

Alejandra Sánchez-Quintero; Barry M. Bradford; Rick Maizels; David S. Donaldson; Neil A. Mabbott. Effect of co-infection with a small intestine-restricted helminth pathogen on oral prion disease pathogenesis in mice. Scientific Reports 2019, 9, 6674 .

AMA Style

Alejandra Sánchez-Quintero, Barry M. Bradford, Rick Maizels, David S. Donaldson, Neil A. Mabbott. Effect of co-infection with a small intestine-restricted helminth pathogen on oral prion disease pathogenesis in mice. Scientific Reports. 2019; 9 (1):6674.

Chicago/Turabian Style

Alejandra Sánchez-Quintero; Barry M. Bradford; Rick Maizels; David S. Donaldson; Neil A. Mabbott. 2019. "Effect of co-infection with a small intestine-restricted helminth pathogen on oral prion disease pathogenesis in mice." Scientific Reports 9, no. 1: 6674.

Journal article
Published: 27 February 2019 in Journal of Experimental Medicine
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Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell–dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell–dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell–dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota.

ACS Style

Felipe Melo Gonzalez; Hana Kammoun; Elza Evren; Emma E. Dutton; Markella Papadopoulou; Barry M. Bradford; Ceylan Tanes; Fahmina Fardus-Reid; Jonathan R. Swann; Kyle Bittinger; Neil A. Mabbott; Bruce A. Vallance; Tim Willinger; David R. Withers; Matthew R. Hepworth. Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria. Journal of Experimental Medicine 2019, 216, 728 -742.

AMA Style

Felipe Melo Gonzalez, Hana Kammoun, Elza Evren, Emma E. Dutton, Markella Papadopoulou, Barry M. Bradford, Ceylan Tanes, Fahmina Fardus-Reid, Jonathan R. Swann, Kyle Bittinger, Neil A. Mabbott, Bruce A. Vallance, Tim Willinger, David R. Withers, Matthew R. Hepworth. Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria. Journal of Experimental Medicine. 2019; 216 (4):728-742.

Chicago/Turabian Style

Felipe Melo Gonzalez; Hana Kammoun; Elza Evren; Emma E. Dutton; Markella Papadopoulou; Barry M. Bradford; Ceylan Tanes; Fahmina Fardus-Reid; Jonathan R. Swann; Kyle Bittinger; Neil A. Mabbott; Bruce A. Vallance; Tim Willinger; David R. Withers; Matthew R. Hepworth. 2019. "Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria." Journal of Experimental Medicine 216, no. 4: 728-742.

Journal article
Published: 05 February 2019 in Journal of Experimental Medicine
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Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.

ACS Style

Alice E. Denton; Silvia Innocentin; Edward J. Carr; Barry M. Bradford; Fanny Lafouresse; Neil A. Mabbott; Urs Mörbe; Burkhard Ludewig; Joanna R. Groom; Kim L. Good-Jacobson; Michelle A. Linterman. Type I interferon induces CXCL13 to support ectopic germinal center formation. Journal of Experimental Medicine 2019, 216, 621 -637.

AMA Style

Alice E. Denton, Silvia Innocentin, Edward J. Carr, Barry M. Bradford, Fanny Lafouresse, Neil A. Mabbott, Urs Mörbe, Burkhard Ludewig, Joanna R. Groom, Kim L. Good-Jacobson, Michelle A. Linterman. Type I interferon induces CXCL13 to support ectopic germinal center formation. Journal of Experimental Medicine. 2019; 216 (3):621-637.

Chicago/Turabian Style

Alice E. Denton; Silvia Innocentin; Edward J. Carr; Barry M. Bradford; Fanny Lafouresse; Neil A. Mabbott; Urs Mörbe; Burkhard Ludewig; Joanna R. Groom; Kim L. Good-Jacobson; Michelle A. Linterman. 2019. "Type I interferon induces CXCL13 to support ectopic germinal center formation." Journal of Experimental Medicine 216, no. 3: 621-637.