Kathryn J. Else

University of Manchester

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Ruth Forman

University of Manchester

Richard K. Grencis

University of Manchester

Sheena M. Cruickshank

University of Manchester

Iris Mair

University of Edinburgh

Janette E. Bradley

University of Nottingham

David B. Sattelle

University College London

Matthew L. deSchoolmeester

University of Manchester

Hannah Smith

University of Manchester

Frederick A. Partridge

University College London

Larisa Logunova

University of Manchester

Cooperative Institutions

University of Manchester

149

Manchester Academic Health Science Centre

University of Edinburgh

University of Oxford

University of Nottingham

Institute of Immunology

Imperial College London

University of Cambridge

Centre National de la Recherche Scientifique

Centre for Inflammation Research

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Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase

Scientific Reports (2020)

David S. Donaldson Barry Bradford Kathryn J. Else Neil A. Mabbott

Abstract 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.

Pathogenesis

10.1038/s41598-020-61483-4

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Citations (17)

Immunity to coccidiosis: genetic influences on lymphocyte and cytokine responses to infection with Eimeria vermiformis in inbred mice

Parasite Immunology (1993)

D. Wakelin Mark E. Rose Patricia Hesketh Kathryn J. Else R. K. Grencis

SUMMARY Cellular and cytokine responses to infection with Eimeria vermiformis were compared in BALB/c (resistant) and C57BL/6 (B6‐susceptible) inbred mice. Cellular responses in the mesenteric lymph node (MLN) occurred sooner after primary infection in the resistant BALB/c strain. In contrast, proliferative responses occurred earlier after challenge in B6 mice. Resting levels of CD4 + ve and CD8 + ve T‐lymphocytes in the MLN differed between the two strains but the relative numbers of each subset remained relatively constant throughout primary infection. MLN cells taken at intervals after infection were assayed for release of the cytokines IFN‐gamma, IL‐5 and IL‐10 after culture in vitro with the mitogen Concanavalin A (Con‐A) or with parasite antigen. With either stimulus cells from resistant BALB/c mice released IFN‐gamma and IL‐5 earlier after infection than did B6 cells. The strains had a comparable absolute ability to produce IFN‐gamma but BALB/c cells released more IL‐5 than did B6, levels declining, rather than increasing, during primary infection in the latter. Only cells from BALB/c mice released IL‐10 during infection. Cells taken after a secondary infection released relatively little cytokine after pulsing in vitro. These data suggest that the difference in response phenotype between the two strains when infected with E. vermiformis reflect a kinetic, rather than a qualitative, difference in ability to mount protective T‐helper (Th) cell subset responses. No evidence was found for a Th2‐mediated interference with ability to release IFN‐gamma, the cytokine most closely associated with protective immunity.

Cellular immunity

10.1111/j.1365-3024.1993.tb00567.x

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Embracing nature’s complexity: Immunoparasitology in the wild

Seminars in Immunology (2021)

Iris Mair Tom N. McNeilly Yolanda Corripio‐Miyar Ruth Forman Kathryn J. Else

A wealth of research is dedicated to understanding how resistance against parasites is conferred and how parasite-driven pathology is regulated. This research is in part driven by the hope to better treatments for parasitic diseases of humans and livestock, and in part by immunologists who use parasitic infections as biomedical tools to evoke physiological immune responses. Much of the current mechanistic knowledge has been discovered in laboratory studies using model organisms, especially the laboratory mouse. However, wildlife are also hosts to a range of parasites. Through the study of host-parasite interactions in these non-laboratory systems we can gain a deeper understanding of parasite immunology in a more natural, complex environment. With a focus on helminth parasites, we here explore the insights gained into parasite-induced immune responses through (for immunologists) non-conventional experimental systems, and how current core findings from laboratory studies are reflected in these more natural conditions. The quality of the immune response is undoubtedly a central player in susceptibility versus resistance, as many laboratory studies have shown. Yet, in the wild, parasite infections tend to be chronic diseases. Whilst reading our review, we encourage the reader to consider the following questions which may (only) be answered by studying naturally occurring parasites in the wild: a) what type of immune responses are mounted against parasites in different hosts in the wild, and how do they vary within an individual over time, between individuals of the same species and between species? b) can we use wild or semi-wild study systems to understand the evolutionary drivers for tolerance versus resistance towards a parasite? c) what determines the ability of the host to cope with an infection and is there a link with the type of immune response mounted? d) can we modulate environmental factors to manipulate a wild animal's immune response to parasitic infections, with translation potential for humans, wildlife, and livestock? and e) in context of this special issue, what lessons for Type 2 immunity can we glean from studying animals in their natural environments? Further, we aim to integrate some of the knowledge gained in semi-wild and wild settings with knowledge gained from traditional laboratory-based research, and to raise awareness for the opportunities (and challenges) that come with integrating a multitude of naturally-occurring variables into immunoparasitological research.

10.1016/j.smim.2021.101525

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PAR volume 145 issue 7 Cover and Back matter

Parasitology (2018)

Julie Healer Chris Chiu Diana S. Hansen James O’Sullivan Julia Behnsen

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Content (measure theory)

10.1017/s0031182018001099

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The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis

Journal of Virology (2015)

David S. Donaldson Kathryn J. Else Neil A. Mabbott

Prion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease.Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence.

Pathogenesis

Microfold cell

Gut-associated lymphoid tissue

Intestinal mucosa

10.1128/jvi.01544-15

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Citations (41)

Host protective immunity to Trichinella spiralis in mice: activation of Th cell subsets and lymphokine secretion in mice expressing different response phenotypes.

PubMed (1991)

Richard K. Grencis Lothar Hültner Kathryn J. Else

Host protective immunity to the intestinal dwelling nematode Trichinella spiralis is mediated by CD4+ mesenteric lymph node (MLN) cells during the course of intestinal infection. The present study has examined the cytokine production by T cells within the MLN of two H-2-compatible strains of mice infected with T. spiralis which differ in the speed at which they expel the parasite from the gut. For both strains of mice, in vitro stimulation of MLN cells with a protective worm antigen preparation resulted in secretion of elevated levels of interleukin-3 (IL-3), IL-4, IL-5 and IL-9 compared to controls. Negligible levels of interferon-gamma (IFN-gamma) were secreted. Furthermore, a similar pattern of cytokine secretion was observed from MLN cells taken from infected mice after in vitro stimulation by T-cell mitogens. No evidence was found for a relationship between quantity of cytokine secreted and the differences in speed of parasite expulsion in the two strains of mice studied. The results support the hypothesis that protective immunity to T. spiralis infection is associated with the activation of Th2-type cells within the MLN in the relative absence of Th1-type cells.

Trichinella spiralis

Trichinella

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Peripheral Cytokine Responses toTrichuris murisReflect Those Occurring Locally at the Site of Infection

Infection and Immunity (2000)

Matthew D. Taylor Catherine J. Betts Kathryn J. Else

ABSTRACT The study of human cellular immune responses to parasite infection under field conditions is very complex. Often, the only practical site from which to sample the cellular responses is the peripheral blood. Sampling peripheral blood lymphocytes (PBL) relies on the assumption that these peripheral responses accurately reflect the immune responses acting locally at the site of infection. This is a particularly important point for the human intestinal helminth Trichuris trichiura , which solely inhabits the cecum and large intestine and so will stimulate a localized immune response. Using the well-defined model of T. trichiura , T. muris in the mouse, we have demonstrated that the dominant cytokine responses of the mesenteric lymph nodes (MLN) can be detected by sampling PBL. Resistant mice which mount a type 2 cytokine response in their MLN had PBL producing interleukin-4 (IL-4), IL-5, and IL-9, with negligible levels of gamma interferon (IFN-γ). Conversely, susceptible mice which mount a type 1 cytokine response in their MLN had PBL producing IFN-γ and negligible levels of type 2 cytokines. We have also shown that the PBL are capable of mounting a functional immune response against T. muris . PBL from immune mice were capable of transferring immunity to T. muris -infected severe combined immunodeficient (C.B-17 scid/scid ) mice. Sampling PBL responses is therefore a viable option for monitoring human intestinal immune responses during T. trichiura infection in the field.

Trichuris trichiura

Trichuriasis

Cecum

10.1128/iai.68.4.1815-1819.2000

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Eosinophils Are Crucial for Mediating the Anticontractile Capacity of Perivascular Adipose Tissue

Circulation (2013)

Sarah Withers Ruth Forman Kathryn J. Else Selene Meza‐Perez William W. Agace

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Issue Information

Parasite Immunology (2023)

Eleanor M. Riley Richard K. Grencis P Cooper Angus W. MacDonald Helena Helmby

aims and scope Parasite Immunology is an international journal devoted to research on all aspects of parasite immunology in human and animal hosts.Emphasis has been placed on how hosts control parasites, and the immunopathological reactions which take place in the course of parasitic infections.The Journal welcomes original work on all parasites, particularly helminths, protozoa and ectoparasites.

10.1111/pim.12931

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Morphological variability in the mucosal attachment site of Trichuris muris revealed by X-ray microcomputed tomography

bioRxiv (Cold Spring Harbor Laboratory) (2021)

James D.B. O’Sullivan Sheena M. Cruickshank Philip J. Withers Kathryn J. Else

Abstract Parasitic infections can be challenging to study, because light and electron microscopy are often limited in visualising complex and inaccessible attachment sites. Exemplifying this, Trichuris spp. inhabits a tunnel of epithelial cells within the host caecum and colon. A significant global burden of this infection persists partly because available anthelminthics lack efficacy, although the mechanisms underlying this remain unknown. Consequently, there is a need to pioneer new approaches to better characterize the parasite niche within the host and investigate how variation in its morphology and integrity may contribute to resistance to therapeutic intervention. To address these aims, we exploited 3D X-ray micro-computed tomography (microCT) to image the mouse whipworm T. muris in caeca of wild-type C57BL/6 and SCID mice ex vivo . Using osmium tetroxide staining to effectively enhance contrast of worms, we found that a subset exhibited preferential positioning towards the bases of the intestinal crypts. Moreover, in one rare event, we demonstrate whipworm traversal of the lamina propria. This morphological variability contradicts widely accepted conclusions from conventional microscopy of the parasite niche, showing Trichuris in close contact with the host proliferative and immune compartments that may facilitate immunomodulation. Furthermore, by using a skeletonization-based approach we demonstrate considerable variation in tunnel length and integrity which may represent an indicator of tunnel “health”. The qualitative and quantitative observations provide a new morphological point of reference for future in vitro study of Trichuris- host interactions and highlight the potential of microCT to more accurately characterise enigmatic host-parasite interactions. Author Summary Parasites are often difficult to observe once established within host tissues, presenting a barrier to biological understanding and therapeutic innovation. Whipworms ( Trichuris spp.) affect 500 million people worldwide, causing significant disability, and appear partially resistant to widely used “deworming” drugs. However, the inaccessibility of worms within the cells of the host intestine makes them highly challenging to image and study. By investigating Trichuris attachment sites in 3D, using X-ray micro-computed tomography, we found that the niche is highly variable in size and, contrary to reports in all previous studies, can also penetrate different layers of intestinal tissue. By showing that worms are positioned much closer to host immune cells that previously appreciated, we provide a morphological reference point for future studies on how Trichuris effectively avoids clearance by the host. The non-invasive imaging approach used represents an excellent opportunity to clarify the lifecycles of other difficult-to-study parasites.

Trichuris

Lamina propria

10.1101/2021.01.07.425704

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