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Page de résumé pour ULgetd-05232007-161528

Auteur : Bras Martins Faisca, Rui Pedro
E-mail de l'auteur : faiscapedro@netcabo.pt
URN : ULgetd-05232007-161528
Langue : Anglais/English
Titre : Experimental infection of inbred mice (Mus musculus) strains by Sendai virus reveals a wide spectrum of innate resistance/susceptibility patterns.
Intitulé du diplôme : Doctorat en sciences vétérinaires
Département : FMV - Département de morphologie et pathologie
Jury :
Nom : Titre :
Antoine, Nadine Membre du jury/Committee Member
Art, Tatiana Membre du jury/Committee Member
Clercx, Cécile Membre du jury/Committee Member
Coignoul, Freddy Membre du jury/Committee Member
Crespeau, François Membre du jury/Committee Member
Draye, Mallory Membre du jury/Committee Member
Georges, Michel Membre du jury/Committee Member
Kerkhofs, Pierre Membre du jury/Committee Member
Thiry, Etienne Membre du jury/Committee Member
Leroy, Pascal Président du jury/Committee Chair
Desmecht, Daniel Promoteur/Director
Mots-clés :
  • mouse
  • paramyxovirus
  • Sendai
  • innate resistance
Date de soutenance : 2007-05-30
Type d'accès : Public/Internet
Résumé :

When I first arrived in Liège, the scientific activities of our laboratory focused on the identification of candidate-genes whose different alleles interfere with the resistance/susceptibility of animals against infectious diseases. Two genes were being intensively studied (Mx and OAS) due to their theoretical potential in interfering with the replicative cycle of several viruses responsible for bovine’s viral pneumonias (Baise et al., 2004 ; Gerardin et al., 2004 ; Leroy et al., 2005 ; 2006).

My work consisted then, in the identification of other genes potentially implicated in the resistance against the Paramyxoviruses. The Paramyxoviridae family includes some of the great and ubiquitous disease-causing viruses of animals, including the bovine parainfluenza type 3, the bovine respiratory syncytial virus, the Newcastle disease virus, the distemper virus, etc. Evidence was accumulating that genetic factors were involved both in the control of infectious diseases (Abel et al., 1991 ; 1995 ; Alcais et al., 1997 ; Jin et al., 1999 ; Martinson et al. 1997 ; Shaw et al., 1995) and in the regulation of infection levels and clinical presentation (Garcia et al., 1999 ; Plancoulaine et al., 2000 ; 2003). Thus, identifying genes that control the organism response to paramyxoviruses was a crucial step in elucidating how they might affect the pathophysiological processes underlying the severity of the disease induced.

Other experiences done in this laboratory showed us how risky and difficult was any extrapolation of the mouse results to another species if these results were brought through infection with a heterologous virus, so we decided to implement this strategy with Sendai virus (SeV), the archetype organism of the Paramyxoviridae family, from which most of the basic biochemical, molecular and biologic properties of the whole family were derived from (Chanock et al., 2001).

With this goal in mind my thesis was divided in five successive steps:

In order to establish a standard model of SeV infection, the first step consisted in determining the best volume of inoculum that was needed to achieve a safe, reproducible pulmonary deposition of Sendai virus in the mice lungs.

Secondly we developed a murine model of SeV infection using a series of different and sophisticated procedures that allowed a quantitative assessment of disease severity and progression.

Then we compared SeV infections among 6 strains of mice that were deliberately chosen because they originated from different lineages, as deduced from known genealogical and

phylogenetic data. Applying these procedures to distinct inbred strains of mice, revealed highly significant differences in susceptibility between them. More specifically 129/Sv were highly susceptible while BALB/c were particularly resistant, BALB/c exhibiting a benign and asymptomatic affection of the epithelium of the airways, with no functional impact, generating slight mononucleated cell infiltration, in which viral replication is repressed and the virus swiftly eliminated.

As a result, in the fourth part of my study we discussed a series of hypotheses that should be tested in the future to improve our understanding of why BALB/c is so resistant to SeV infection. Practically speaking, our studies led to the gathering of a genomic DNA collection from the parental extreme lines in terms of susceptibility (129/Sv) and resistance (BALB/c) and their F1 and F2 offspring. Within this bank, each of the 263 DNA sample is associated with a portfolio of phenotypic values that are estimators of the resistance each mouse opposed to the SeV. We hope that, between expert hands, this bank will allow the detection of genes of which the alleles contribute, at least in part, to the spectacular resistance of BALB/c.

The last part of my thesis consisted in applying our model to establish if the receptor TLR4 influenced the pathophysiology of the Paramyxoviridae in general. Because the role of this receptor had already been excluded for SeV, we tested another virus of the same family and homologous for the mice, the PVM (standing for pneumonia virus of mice). This work showed, in contradiction of what had been found in heterologous models in the past, that TLR4 is not involved in host defense against respiratory tract infection with the Paramyxoviridae.

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