Certains virus parviennent à infecter un organisme de manière chronique. Ils peuvent persister dans un tissu malgré la réponse immunitaire et la production d’interféron, une substance produite par nos cellules qui est critique pour notre protection contre les infections virales. Etudier comment les virus contournent ces défenses permet de mieux comprendre le fonctionnement du système immunitaire lui-même et d’envisager de moduler son activité pour traiter ses dysfonctionnements et certaines infections virales.

 

Les infections virales persistantes

Nous sommes tous porteurs d’au moins une dizaine de virus qui infectent notre organisme de façon persistante. Par exemple, 70 à 90% de la population mondiale est porteuse de virus Herpès comme le virus Herpes simplex 1 qui provoque les « boutons de fièvre » bien connus ou le virus Epsteinn-Barr qui cause la mononucléose infectieuse et peut occasionnellement être responsable de tumeurs ou d’infections dramatiques du système nerveux. Certains virus persistants ne provoquent aucune pathologie. D’autres, comme le virus de l’hépatite C ou le virus du SIDA peuvent induire des maladies chroniques graves.
 

La réponse interféron

Parmi les défenses de notre organisme contre les infections virales, l’interféron occupe une place de choix. Il s’agit d’une famille de molécules sécrétées par les cellules infectées, qui ont pour but d’alerter les cellules voisines et de les rendre résistantes au virus. Un dysfonctionnement du système interféron peut être la cause d’infections virales catastrophiques, notamment d’encéphalites causées par le virus herpès simplex 1.
 

L’évolution virale et l’échappement à la réponse immunitaire

Par leur cycle de multiplication rapide, les virus évoluent de manière remarquablement efficace. L’adaptation des virus à infecter leur hôte est fascinante. La plupart des virus expriment notamment des protéines destinées à interférer avec le système immunitaire de l’hôte. En particulier, les virus persistants ont développé des stratégies qui leur permet d’échapper aux armes du système immunitaire en agissant sur des cibles clés de ce système.

En étudiant comment les virus contrecarrent la réponse immunitaire, on peut donc mettre le doigt sur des éléments critiques de la réponse immunitaire et mieux comprendre son fonctionnement.
 

Projet de recherche : "Persistance virale et réponse interféron"

Notre projet de recherche comporte deux volets : d’une part, nous étudions un virus murin, le virus de Theiler, qui est capable de persister dans le système nerveux malgré une forte réponse immunitaire. La présence du virus dans le système nerveux et la réponse inflammatoire qu’il engendre provoquent des lésions proches de celles de la sclérose en plaques chez l’homme. Nous étudions plus spécifiquement comment le virus arrive à persister en dépit de la réponse immune. Nous étudions les mécanismes par lesquels certaines protéines codées par le virus interfèrent avec le système immunitaire de l’hôte. Par ailleurs, nous étudions le fonctionnement de la réponse interféron de l’hôte, vu le rôle critique qu’elle joue contre les infections virales.

Viral persistence, immune evasion and interferon response

Owing to their fast evolution, viruses developped fascinating strategies to infect and replicate in their host. To escape immune defenses, persistent viruses express proteins that evolved to target key components of the immune system.

Much mechanistic insight into our own immune system can thus be gained by studying how viral proteins act to interfere with immune responses.

The molecular virology group focuses on two topics related to the interplay between viral infections and the immune response of the host.

1. Theiler’s virus : We analyze the model infection of the central nervous system by Theiler's virus (TMEV or Theiler's murine encephalomyelitis virus). This virus can escape the immune defenses of the host and provoke a persistent infection of the central nervous system which can lead to a chronic demyelinating disease considered as a model of multiple sclerosis. We study the role of viral proteins that antagonize the innate immune response of the host, thus allowing the virus to persist.

2. Interferons (IFNs) : We analyze the innate immune response against viral pathogens in the particular context of the central nervous system. We focus our analysis on the type I interferon (IFN-α/β) and on the recently discovered type III interferon (IFN-λ) responses which are critically important to control viral infections and modulate the acquired immune response.

 

1. Persistent infection of the central nervous system by Theiler's virus

Theiler’s murine encephalomyelitis virus (TMEV or Theiler’s virus) is a murine picornavirus showing a striking ability to persist in the central nervous system of the host in spite of a specific cellular and humoral immune response. Persistence of the virus is associated with a strong inflammatory response and with lesions of primary demyelination reminiscent of those found in human multiple sclerosis (Brahic et al., Annu rev. Microbiol., 2005). Our work aims at understanding how a virus can persist in the central nervous system (CNS) of an immunocompetent host, thus evading the immune response.

We currently analyze the function of two viral proteins, namely L and L*, that are critical for persistence of the virus in the central nervous system though they are not required for replication of the virus in cell culture. Hence, these proteins are believed to interact with host factors in vivo and to counteract the host immune defenses.

L Protein: The leader (L) protein encoded by Theiler's virus is a 76 amino acid-long peptide containing a zinc-binding motif. In spite of its small size, this protein exerts several important activities. It inhibits the production of IFN-α/β by infected cells (van Pesch et al., J. Virol. 2001), affects the nucleo-cytoplasmic trafficking of host proteins (Delhaye et al., J. Virol. 2004) and prevents the formation of stress granules (Borghese et al. J. Virol. 2011). A structure-function analysis of the L protein is underway to identify the functional motifs of the L protein and to further decipher its mode of action.

L* Protein: Protein L* of Theiler's virus is unique among picornaviruses in that it is translated from an alternative open reading frame overlapping the ORF encoding the viral polyprotein. Translation of both the viral polyprotein and the L* protein depends on a Ribosome Internal Entry Site (IRES) located in the 5' non-coding region of the genome.
 We showed that the L* protein is required for long term persistence of the virus in the central nervous system. In vitro, L* facilitates the infection of macrophages (van Eyll et al. J. Virol. 2000, 2002). L* is partly cytosolic and partly anchored in the mitochondrial outer membrane (Sorgeloos et al., J. Virol. 2011). In the cytosol, L* inhibits the activity of RNase L, one of the best-characterized effector of the IFN response (Sorgeloos et al., PloS pathog. 2013 ; Drappier and Michiels, Curr. Op. Virol. 2015).  We currently analyze the mechanisms of RNase L inhibition.

 

2. Innate immunity (in the central nervous system): role of type I (IFN-α/β) and type III (IFN-λ) interferons

Type I interferons (IFNs) are a family of cytokines that play a critical role in the defense of the organism against viral infection. In spite of their sequence divergences, all type I IFNs (IFN-α, IFN-β, IFN-κ, IFN-ε IFN-ω...) bind the same heterodimeric receptor made of the IFNAR-1 and IFNAR-2c subunits. IFN binding to the receptor activates the JAK/STAT pathway and triggers the transcriptional upregulation of many genes called ISGs (Interferon Stimulated Genes). The proteins encoded by these genes (Mx, PKR, OAS...) are responsible for the antiviral, cytostatic and immunomodulatory activities of type I IFNs. However, dysregulation of IFN production can have adverse effects and induce diseases referred to as interferonopathies. We currently analyze gene mutations responsible for the Aicardi-Goutières syndrome, where excess IFN production is responsible for a crippling developmental disease.

Type III IFNs (also called IL-28/IL-29 or IFNs-λ) were discovered recently. They bind to a receptor distinct from that of type I IFNs, made of the IL10Rβ and IL28Rα subunits. In spite of this different receptor usage, type III IFNs activate the same signal transduction pathway as type I IFNs and activate the same set of interferon stimulated genes.

 Our group analyzes the reason for the multiplicity of type I IFN genes and for the apparent redundancy of the type I and type III IFN systems.

Expression of IFNAR, the type I IFN receptor is widespread and most cells of the body can respond to these IFNs. In contrast, the response to IFN-λ exhibits striking tissue and cell specificity. In the analyzed tissues, response to circulating IFN-λ was restricted to epithelial cells (Sommereyns et al., PloS Pathog. 2008). This suggests that IFN-λ evolved as a specific protection of epitheliums and mucosae. Accordingly, IFN-l was shown to exert a major role in the defense against rotavirus infection (Pott et al., PNAS 2011). Our current research work addresses the relevance of such tissue and cell specificities of IFN responses (for review, see Hermant et al., J. Innate Immun., 2014).


Production of IFNs in the CNS :
 We observed that the relative production of IFN-λ (over that of IFN-α/β) was low in the brain of mice infected with neurotropic viruses. Thus, the central nervous system appears to be both a poor producer of IFN-λ and a poor responder to this cytokine.
 In contrast, IFN-α/β is readily produced in the central nervous system and we showed that neurons were able to contribute to the production of these IFNs (Delhaye et al., PNAS, 2006) although they appear to be much less potent than astrocytes at producing IFN (Pfefferkorn et al., J. Virol . 2015). Neurons also appear to have a restricted IFN response, some ISGs, such as Apolipoprotein L9, being specifically not or little expressed in neurons (Kreit et al. J. Virol. 2014).

Complete list on PubMed
Thomas Michiels
Institut de Duve
Avenue Hippocrate 75 - B1.74.07
B-1200 Bruxelles
Tel:
+32 2 764 74 29
Fax:
+32 2 764 74 95
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