Soutenance publique de thèse de doctorat en Sciences biologiques - Emeline BARBIEUX

Development of candidate vaccines against Brucella melitensis and Acinetobacter baumannii infections in a mouse model

Jury

• Prof. Thierry ARNOULD (département de biologie, UNamur), président
• Prof. Xavier DE BOLLE (département de biologie, UNamur), promoteur et secrétaire
• Prof. Laurence VAN MELDEREN (faculté des sciences, ULB), co-promotrice
  
• Prof. Anne BOTTEAUX (faculté de médecine, ULB)
  
• Prof. Charles VAN DER HENST (Center for Structural Biology, VUB)
  
• Dr David O’CALLAGHAN (CNR Brucella UFR Medecine, Université de Montpellier)
  
• Dr Eric MURAILLE (faculté de médecine, ULB)

Abstract

Facultative intracellular bacteria of the Brucella genus cause brucellosis, a zoonotic infection with a significant socioeconomic impact in southern countries. The recommended live attenuated vaccines (LAV) against brucellosis, Rev.1 and S19, provide satisfactory protection for livestock but can induce abortions and are virulent for humans. This situation causes serious economic losses and human infections. These first-generation LAVs were generated by empirical methods such as random attenuation by successive passages. The transposon sequencing (Tn-seq) approach offers a new avenue for the rational development of safer LAVs. Indeed, the Tn-seq approach makes it possible to predict the genes required by the bacteria to grow in different conditions such as culture medium, cell infection (in vitro) and mice infection (in vivo). These genes can then be deleted to weaken the strain and try to select new LAV candidates. Our results demonstrate that Brucella melitensis faces different selection pressures depending on the infected organ. Based on our Tn-seq data, we selected genes whose deletion generates strains capable of multiplying temporarily in the lungs and the spleen and inducing protective immunity but without establishing themselves permanently in the spleen, the main reservoir organ. We tested the persistence and the induced immune protective memory of a plsC gene deletion mutant, involved in the biosynthesis of membrane phospholipids. We observed that this mutant induces similar protection but persists less in the spleen than the reference Rev.1 vaccine, which suggests that it could be safer.

Acinetobacter baumannii is a bacterium responsible for serious nosocomial infections, including pneumonia, mainly affecting immunocompromised individuals. The outbreak of drug multi-resistant A. baumannii strains to antibiotics makes the development of a vaccine against this pathogen essential. In an intranasal infection model in mice, vaccination with the inactivated LAC-4 or AB5075 strain induces the development of immunity against a challenge with the live LAC-4 strain. We observed that intranasal vaccination with the inactivated LAC-4 strain partially protects mice genetically deficient for key elements of the adaptive immune response as well as mice treated with cyclophosphamide, an immunosuppressive drug frequently used in human treatment. These results suggest that vaccination with an inactivated A. baumannii strain could protect at-risk populations of immunocompromised patients.

 

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