Murid herpesvirus 4 infection protects mice from the development of an anti-pneumovirus vaccine-induced TH2 immunopathology

Gammaherpesvirus imprintin

Impact de l’Imprégnation Immunitaire de l’Herpèsvirus Murin 4 sur le Développement d’Immunopathologies Respiratoires Hétérologues

Gammaherpesvirus (ɣ-HVs) infections are highly prevalent in both human and animals. They persist in their host by establishing and maintaining latent infections. Murid herpesvirus 4 (MuHV-4) is a wild rodent pathogen that can be used as a model of ɣ-HV infection in the laboratory mouse. Like other ɣ-HVs, MuHV-4 profoundly imprints the host immune system to allow completion of its biological cycle. In particular, MuHV-4-induced modulations have been shown to confer bystander protection against heterologous secondary infections. Type 2 respiratory immunopathologies are of major interest in public health, specifically in developped countries. Notably, allergic asthma affects more than 300 million people worldwide and hSRV (human respiratory syncytial virus) inactivated vaccine-induced Th2 immunopathology substantially delays the development of vaccines against this virus which is yet the main infectious agent of bronchopneumopathies in children and olders. According to the hygiene hypothesis, epidemiological studies suggest that late primoinfections to human ɣ-HVs are correlated to an increased risk of allergic sensitization later in life. Using the MuHV-4 model, the in vivo impact of a ɣ-HV infection was tested against the development of on one hand, allergic airway inflammation induced by house dust mites (HDM) allergens (study 1) and on the other hand, anti-pneumovirus Th2 immunopathology, using Pneumonia virus of mice (PVM) to faithfully mimic the original hRSV disease in homologous host-virus model (study 2). Our results have shown that MuHV-4-infected mice are protected from the development of both allergic and vaccine-induced type 2 immune disorders. Moreover, MuHV-4-infected mice were also clinically protected from the subsequent heterologous infection with PVM. Finally, the protective mechanism against HDM allergic asthma was deciphered; pulmonary MuHV-4 lytic infection causes the severe depletion of the alveolar niche which is repopulated by bone marrow-derived monocytes. These latter cells then differentiate into alveolar macrophages (AMs) that are both phenotypically and functionally distinct from resident AMs. Indeed, in previously MuHV-4 infected mice, these monocyte-derived AMs express regulatory functions to block the activation of dendritic cells involved in allergic sensitization, therefore, conferring protection against allergic airway inflammation. In conclusion, the present thesis has unambiguously unraveled that ɣ-HV infection can protect the host against the development of main public health-related respiratory type 2 immune disorders. Replacement of embryonic AMs by regulatory monocytes is thus a major feature underlying the long-term training of the lung immunity after infections, and could provide a possible mechanistic explanation for the hygiene hypothesis. Altogether, this work opens interesting perspectives for the prevention of respiratory type 2 immunopathologies.Les gammaherpèsvirus (ɣ-HVs) sont des virus extrêmement prévalents, tant chez l’homme que chez les animaux. Ils infectent leur hôte de façon persistante suite à l’établissement et au maintien d’une infection latente. L’herpèsvirus murin 4 (MuHV-4) est un pathogène naturel de rongeurs et un modèle d’infection par un gammaherpèsvirus chez la souris de laboratoire. Comme tous les ɣ-HVs, le MuHV-4 module profondément le système immunitaire de son hôte en vue d’accomplir son cycle biologique. En particulier, il a été observé que ces modulations peuvent conférer à l’hôte une protection inattendue contre certains pathogènes hétérologues. Les immunopathologies respiratoires de type 2 sont une source de préoccupation majeure en santé publique, spécifiquement dans les pays développés. Notamment, l’asthme allergique affecte plus de 300 millions de personnes dans le monde et l’immunopathologie de type 2 induite par les vaccins inactivés hRSV (virus respiratoire syncytial humain) a considérablement retardé le développement de vaccins à l’encontre de ce virus qui est pourtant un agent majeur des broncho-pneumopathies infectieuses chez les enfants et les personnes âgées. Dans le contexte de l’hypothèse de l’hygiène, des données épidémiologiques chez l’homme suggèrent qu’une infection primaire plus tardive aux ɣ-HVs humains favoriserait le développement ultérieur de sensibilisations allergiques. En utilisant le modèle MuHV-4, nous avons testé in vivo l’impact de l’infection par un ɣ-HV sur le développement d’une part, d’une inflammation respiratoire allergique induite par des extraits d’acariens (HDM) (étude 1) et d’autre part, d’une immunopathologie Th2 anti-pneumovirus, grâce à un modèle hôte-virus homologue utilisant le pneumovirus murin (PVM) pour reproduire la pathologie hRSV originale (étude 2). Au travers des deux études, nos résultats ont démontré que les souris infectées par le MuHV-4 sont protégées du développement de pathologies respiratoires de type 2 allergique ou vaccinale. En outre, nous avons observé que le MuHV-4 confère une protection clinique à l’encontre d’une infection hétérologue subséquente par le PVM. Enfin, le mécanisme de protection de l’asthme allergique a été caractérisé; le cycle lytique pulmonaire du MuHV-4 entraîne une déplétion sévère de la niche alvéolaire, qui est repeuplée par des précurseurs monocytaires dérivés de la moelle osseuse se différentiant en macrophages alvéolaires (AMs) différents des AMs résidents tant au niveau phénotypique que fonctionnel. En effet, chez les souris préalablement infectées par le MuHV-4, ces AMs dérivant des monocytes expriment des propriétés régulatrices qui bloquent l’activation des cellules dendritiques impliquées dans la sensibilisation allergique et qui, in fine, médient le phénotype protecteur. En conclusion, cette thèse a dévoilé que l’infection par un ɣ-HV peut protéger l’hôte du développement de maladies respiratoires de type 2 d’importance en santé publique. Le remplacement des AMs résidents par des monocytes régulateurs est donc un levier majeur de modulation à long terme de l’immunité innée après des infections microbiennes, pouvant contribuer à la compréhension des mécanismes sous-jacents à l’hypothèse de l’hygiène. Finalement, cette thèse offre des perspectives de travail intéressantes dans la recherche thérapeutique contre ces pathologies respiratoires de type 2.Gammaherpesvirus imprintin

Evaluation of urinary and serum level of chemokine (C-C motif) ligand 2 as a potential biomarker in canine urothelial tumours

Chemokine (C-C motif) ligand 2 (CCL2) is a chemotactic cytokine recruiting monocytes, releasing growth factors and promoting adhesion in vascular endothelium. Elevated serum and urinary CCL2 levels and expression of its receptor (CCR2) have been associated with tumorigenesis in human urinary malignancies. CCL2 implication has not been investigated in canine urothelial carcinoma. The aim of this study was to evaluate CCL2 serum and urine levels (measured by ELISA) in dogs with urothelial carcinoma or non-neoplastic urinary tract disease. CCL2 serum and urine levels were significantly higher in diseased dogs compared with healthy dogs (P < 0.001). Dogs with carcinoma had significantly higher serum and urine CCL2 levels (P = 0.001) than healthy dogs. Dogs with metastases showed significantly lower serum and urine CCL2 levels compared with the non-metastasised tumour group (P = 0.007). CCL2 as a diagnostic marker for urothelial carcinoma held a sensitivity of 95.2% and a specificity of 38.2% in the urine. As a staging marker, sensitivity was 85.7% and specificity was 57.1% with a positive predictive value of 75.7% and a negative predictive value of 71.9%. Further investigation is needed to define the role of CCL2 as a prognostic marker in canine urothelial carcinoma. © 2018 John Wiley & Sons Lt

No Evidence of Herpesvirus Infection in West Highland Terriers with Canine Idiopathic Pulmonary Fibrosis

In humans, horses, and rodents, an association between pulmonary fibrotic disorders and gammaherpesvirus infection has been suggested. In dogs, canine idiopathic pulmonary fibrosis (CIPF), a progressive fibrotic lung disease of unknown origin and poorly understood pathophysiology, has been reported to occur in West Highland white terriers (WHWTs). The present study investigated the potential association between CIPF and herpesvirus infection. A PCR assay, using a mixture of degenerate and deoxyinosine-substituted primers targeting highly conserved regions of the DNA polymerase gene (DPOL) of herpesviruses, was applied on both lung and blood samples from WHWTs affected with CIPF and controls. Herpesvirus DPOL sequence could not be amplified from any of 46 lung samples (28 affected WHWTs and 18 control dogs of various breeds) and 38 blood samples (19 CIPF WHWTs and 19 control age-matched WHWTs) included. An association between CIPF and herpesvirus infection is therefore unlikely. Investigation of other causes of the disease is warranted. </jats:p

A gammaherpesvirus licenses CD8+ T cells to protect the host from pneumovirus-induced immunopathologies

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