Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial [version 3; referees: 2 approved]

Antony J. Cutler; Joao Oliveira; Ricardo C. Ferreira; Ben Challis; Neil M. Walker; Sarah Caddy; Jia Lu; Helen E. Stevens; Deborah J. Smyth; Marcin L. Pekalski; Jane Kennet; Kara M.D. Hunter; Ian Goodfellow; Linda S. Wicker; John A. Todd; Frank Waldron-Lynch

doi:10.12688/wellcomeopenres.11300.3

Wellcome Open Research (Oct 2017)

Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial [version 3; referees: 2 approved]

Antony J. Cutler,
Joao Oliveira,
Ricardo C. Ferreira,
Ben Challis,
Neil M. Walker,
Sarah Caddy,
Jia Lu,
Helen E. Stevens,
Deborah J. Smyth,
Marcin L. Pekalski,
Jane Kennet,
Kara M.D. Hunter,
Ian Goodfellow,
Linda S. Wicker,
John A. Todd,
Frank Waldron-Lynch

Affiliations

Antony J. Cutler: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
Joao Oliveira: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Ricardo C. Ferreira: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
Ben Challis: Wellcome Trust/MRC Institute of Metabolic Science, Department of Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK
Neil M. Walker: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Sarah Caddy: Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
Jia Lu: Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
Helen E. Stevens: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Deborah J. Smyth: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Marcin L. Pekalski: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
Jane Kennet: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Kara M.D. Hunter: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK
Ian Goodfellow: Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK
Linda S. Wicker: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
John A. Todd: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
Frank Waldron-Lynch: JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus,Cambridge, CB2 0XY, UK

DOI: https://doi.org/10.12688/wellcomeopenres.11300.3
Journal volume & issue: Vol. 2

Abstract

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Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg), effector T cell (Teff) CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.

Published in Wellcome Open Research

ISSN: 2398-502X (Online)
Publisher: Wellcome
Country of publisher: United Kingdom
LCC subjects: Medicine; Science
Website: https://wellcomeopenresearch.org/

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