A gammaherpesvirus infection can protect against allergic asthma

In a study published today in the journal Nature Immunology, Belgian researchers from the universities of Liège and Ghent (ULiège and UGent) have, for the first time, proven that infecting laboratory mice with a gammaherpesvirus, herpesvirus murin 4 or MuHV-4, protects the latter from developing allergic asthma. This study is the first to prove the crucial role that some viral infections can play in the long-term control of the development of allergic responses.

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mmune responses are traditionally divided into an innate component which is quickly established as non-specific and an adaptive component which takes more time to develop, but which is specific and allows the establishment of the immunological memory. This traditional view has recently been called into question by studies having shown that actors of innate immunity were also modulated in the long term by multiple micro-organisms and microbial derivatives encountered. Therefore, the history of infections in childhood influences the immune responses developed later against completely independent antigens.

In this context, Bénédicte Machiels and Mickaël Dourcy, under the direction of Laurent Gillet (Laboratory of Immunology-Vaccinology (FARAH)), and their colleagues from ULiège and UGent, investigated the imprinting left by the herpesviruses, and more specifically gammaherpesviruses, on the immune system of their host.  In fact, gammaherpesviruses (including the Epstein-Barr virus, responsible for infectious mononucleosis in humans) are very common viruses having co-evolved with their host to establish persistent infections. While these gammaherpesviruses favour regulatory immune responses to maintain their latent state, researchers are interested in the existence of a symbiotic relationship between these agents and their host.

During a pulmonary infection, Murin Herpesvirus 4 causes the death of alveolar macrophages very quickly. Monocytes from the bone marrow are activated and recruited in the lung via the bloodstream. These monocytes are different from alveolar macrophages and persist over the long term. Unlike the resident alveolar macrophages they replace, these alveolar macrophages derived from monocytes present regulatory properties. In fact, they block the ability of dendritic cells in the lung to induce an allergic reaction in response to the administration of House Dust Mite extract © FARAH-GIGA ULiège

In their study published in Nature Immunology, the researchers showed that infecting mice in a laboratory with a gammaherpesvirus, Murid Herpesvirus 4 or MuHV-4, protects the latter from developing allergic asthma. Interestingly, the results obtained revealed that a respiratory infection with MuHV-4 caused the death of alveolar macrophages and the concomitant recruitment of innate immune cells among with monocytes at the inflammation site. These monocytes, originating from bone marrow, were able to reconstitute the alveolar niche and differentiate into mature macrophages in the long term. In addition, unlike alveolar macrophages from non infected individuals, these recruited monocytes presented regulatory properties responsible for the inhibition of the allergic pulmonary response.

These results shine a new light on the origin of populations of macrophages in an infectious context and prove, for the first time, that a viral infection can induce the replacement of a population of resident embryonic macrophages with regulatory monocytes.

In addition, this study highlights the determining effect of antigenic infections or stimulations from a young age for the subsequent development of immune responses, confirming the hygiene hypothesis, according to which the increase in allergies in our countries is a result of the reduction in infections during childhood. Therefore, this study is the first to reveal the crucial role that some viral infections can play in the long-term control of the development of allergic responses. At a time when the incidence of these immunopathologies continues to increase, understanding of the molecular mechanisms at the origin of the regulatory properties induced by gammaherpesviruses could see the emergence of new medical perspectives.

Scientific Reference

“A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.” Nature Immunology, 2017, doi: 10.1038/ni.3857

Bénédicte Machiels ^1,7, Mickael Dourcy ^1,7, Xue Xiao ¹, Justine Javaux ¹, Claire Mesnil ², Catherine Sabatel ², Daniel Desmecht ³, François Lallemand ⁴, Philippe Martinive ⁴, Hamida Hammad ⁵, Martin Guilliams ⁵, Benjamin Dewals ¹, Alain Vanderplasschen ¹, Bart N Lambrecht ^5,6, Fabrice Bureau ² & Laurent Gillet ¹

1. Immunology-Vaccinology, Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine – FARAH, University of Liège
2. Cellular and Molecular Immunology, Department of Functional Sciences, Faculty of Veterinary Medicine – GIGA, University of Liège
3. Department of Pathology, Faculty of Veterinary Medicine – FARAH, University of Liège
4. Department of Radiology, University Hospital Liège, CHU de Liège
5. VIB Center for Inflammation Research, Ghent University
6. Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam
7. These authors contributed equally to this work

Contacts

Prof Laurent GILLET -  Department of Infectious and Parasitic Diseases, Veterinary Vaccinology, FARAH Research Centre part of the Faculty of Veterinary Medicine at the University of Liège.

Tel +32 4 366 42 86 - Email L.Gillet@uliege.be