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Development of vaccine candidates against Brucella melitensis and Acinetobacter baumannii infections in a mouse model

par Barbieux, Emeline
Président du jury Arnould, Thierry
Promoteur Muraille, Eric ;De Bolle, Xavier
Co-Promoteur Van Melderen, Laurence
Publication Non publié, 2023-11-23

Thèse de doctorat

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Résumé :

Facultative intracellular bacteria of the Brucella genus cause brucellosis, a zoonotic infectionwith a significant socioeconomic impact in southern countries. The recommended liveattenuated vaccines (LAVs) against brucellosis, Rev.1 and S19, provide satisfactory protectionfor livestock but can induce abortions and are virulent for humans. This situation causes seriouseconomic losses and human infections. These first-generation LAVs were generated byempirical methods such as random attenuation by successive passages. The transposonsequencing (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 togrow 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 LAVcandidates. Our results demonstrate that Brucella melitensis faces different selection pressuresdepending on the infected organ. Based on our Tn-seq data, we selected genes whose deletiongenerates strains capable of multiplying temporarily in the lungs and the spleen and inducingprotective immunity but without establishing themselves permanently in the spleen, the mainreservoir organ. We tested the persistence and the induced immune protective memory of a plsCgene deletion mutant, involved in the biosynthesis of membrane phospholipids. We observedthat this mutant induces similar protection but persists less in the spleen than the referenceRev.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 drugmulti-resistant A. baumannii strains to antibiotics makes the development of a vaccine againstthis pathogen essential. In an intranasal infection model in mice, vaccination with theinactivated LAC-4 or AB5075 strain induces the development of immunity against a challengewith the live LAC-4 strain. We observed that intranasal vaccination with the inactivated LAC4 strain partially protects mice genetically deficient for key elements of the adaptive immuneresponse as well as mice treated with cyclophosphamide, an immunosuppressive drugfrequently used in human treatment. These results suggest that vaccination with an inactivatedA. baumannii strain could protect at-risk populations of immunocompromised patients.