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S. aureus est un pathogène majeur de l’Homme capable de produire une grande variété de facteurs de virulence tels que les phénol-solubles modulines alpha (PSM) et l’hémolysine delta (Hld). La transmission de S. aureus est essentiellement manu-portée mais les éléments favorisant sa dissémination dans la population restent inconnus. Les mastocytes étant connus pour libérer des médiateurs pruritogènes, nous avons suspecté leur implication dans la physiopathologie et la transmission des infections cutanées staphylococciques. Sur une lignée de mastocytes humains, l’Hld et les PSM1, montrés pour être produits in vivo, déclenchaient la libération de tels médiateurs. Chez S. aureus, la production des toxines est sous la dépendance du système de régulation globale Agr. Les souches de S. aureus appartenant au type Agr1, produisant significativement plus d’Hld et de PSM que les autres souches, ont été les plus fréquemment retrouvées au cours de l’année 2017 dans les infections cutanées staphylococciques. Ceci corrobore l’hypothèse selon laquelle une souche de S. aureus produisant des toxines capables d’interagir avec les mastocytes et induisant un prurit, diffuse plus facilement dans la population. Nous avons ensuite étudié la modulation de l’expression des PSM et d’Hld par des concentrations sub-inhibitrices d’antibiotiques. L’oxacilline induisait une inhibition de l’expression des PSM et d’Hld alors que la clindamycine entraînait plus fréquemment une induction de leur expression. Ces observations nous ont interrogé sur l’utilisation de la clindamycine considérée habituellement comme anti-toxinique et sur l’effet bénéfique ou délétère de l’effet inhibiteur de l’oxacilline / S. aureus is a major human pathogen able to produce several virulence factors such as phenol-solublemodulins alpha (PSMalpha) and delta hemolysin (Hld). S. aureus is essentially spread through hand butthe elements promoting its spreading stay unsolved. Mast cells release several soluble mediatorstriggering itching behavior. We suspect the mast cell involvement in spreading of S. aureus strains andin physiopathology of staphylococcal skin infections. Upon human mast cell line, we showed thatPSMalpha1 and Hld induced the release of mediators triggering itching behavior. Moreover, these toxinswere produced in vivo during staphylococcal skin infections. Expression of staphylococcal virulencefactors is regulated by global regulatory system Agr. Interestingly, we observed that S. aureus strainsbelonging in Agr1 produced higher quantity of PSMalpha and Hld than those belonging to Agr2 and Agr3,and were more frequently responsible to skin infections during the last year. This observation supportsour hypothesis whereby a strain producing toxins able to trigger mast cell mediator inducingscratching behavior, spreads electively in the community. Thereafter, we studied modulation of PSMalphaand Hld expression by sub-inhibitory concentration of antibiotics. We reported that oxacillin inducedan inhibitory effect on PSMalpha and Hld expression, while clindamycin resulted in more frequently aninducer effect. These results are discordant with these observed with Panton-Valentine leucocidin andalpha hemolysin and interrogate on clindamycin use for its anti-toxin activity and on benefic ordeleterious effect of oxacillin inhibitory effect

As a human fungal pathogen, Candida albicans can cause a wide variety of disease conditions ranging from superficial to systemic infections. Many of these infections are caused by an inherent ability of the pathogen to form biofilms on medical devices resulting in high mortality. Biofilms formed by C. albicans are a complex consortium of yeast and hyphal cells embedded in an extracellular matrix and are regulated by a network of transcription factors. Here, I report the role of a novel Zn(II)2-Cys6 binuclear cluster transcription factor, ZCF32, in the regulation of biofilm formation. Global transcriptome analysis reveals that biofilm development is the most altered pathway in the zcf32 null mutant. To delineate the functional correlation between ZCF32 and biofilm development, the set of genes directly regulated by Zcf32 were determined. The data suggest that Zcf32 regulates biofilm formation by repressing the expression of adhesins, chitinases and a significant number of other GPI-anchored proteins. The data presented here establish that there is the lesser recruitment of Zcf32 on the promoters of biofilm genes in biofilm condition compared to the planktonic mode of growth. Thus, the transcription factor ZCF32 negatively regulates biofilm development in C. albicans. Candida albicans, carries an expanded family of Zn(II)2Cys6 transcription factors. A CTG clade-specific protein Zcf32 and its closely related protein Upc2, a well-conserved protein across the various fungal species, belong to this family of proteins. Unlike Upc2, Zcf32 is poorly studied in C. albicans. Here, I examined roles played by these two related transcription factors in biofilm development and virulence of C. albicans. The data show that the null mutants of each of ZCF32 or UPC2 form better biofilms than the wild-type suggesting that both of them negatively regulate the biofilm development. While acting as negative regulators of biofilm formation, these two transcription factors target a different set of biofilm genes. A mouse model of candidiasis reveals that zcf32/zcf32 was hypervirulent while upc2/upc2 shows compromised virulence compared to the wild-type. Notably, the absence of Zcf32 enhances detrimental inflammation brought about by TNFα, IFNβ, and IFNγ. upc2/upc2 failed to generate a similar feedback, instead demonstrated an elevated anti-inflammatory (IL4 and IL10) host response. Taking together, the data exhibit how a recently evolved transcription factor Zcf32 retained functional resemblance with a more ubiquitous member Upc2 but also functionally diverged from the latter in the regulation of virulence of the pathogen.

As ITU são as mais freqüentes infecções ocasionadas por ExPEC. Entre os fatores de virulência (FV) encontram-se nestas cepas adesinas, invasinas, toxinas, sideróforos, e evasinas, localizados em plasmídios ou ilhas de patogenecidade. O objetivo deste estudo foi caracterizar 45 cepas de E. coli isoladas de 33 cães e 7 gatos com ITU, quanto aos sorotipos, FV e grupos filogenéticos. Dos sorogrupos relacionados às ITU foram encontrados O6 (20%), O2 (16%), O25 (4%), O4 e O11 (4% cada um). Entre os genes pesquisados, foram encontrados fimH (100%), pap (47%), sfa (33%) e iha (4%); ibeA (29%); cnf1 (31%), hlyA (27%); fyuA (80%), iucD (22%); traT (51%); cvaC (20%) e malX (67%). Os isolados felinos foram agrupados em B2 (89%) e D (11%), enquanto os caninos em A (5,5%), B1 (19,5%), B2 (55,5%) e D (19,5%). Estes resultados sugerem que as ExPEC isoladas de cães e gatos apresentam potencial patogênico para ocasionar doenças mais graves que as ITU, assim como ocorre em humanos. Além disso, a similitude com as amostras humanas reforça a hipótese acerca de seu potencial zoonótico. / The ability of ExPEC to cause extraintestinal infections in humans, dogs, and cats is associated with the expression of a variety of virulence factors (VF). The aim of this study was to evaluate the frequency of VF related to ExPEC, serotypes, and phylogenetic groups in 45 strains isolated from 33 dogs and 7 cats with UTI. These strains presented serogroups related with extraintestinal infections, e.g. O6 (20%), O2 (16%), O25 (4%), O4 e O11 (each one) and the following genes: fimH (100%), pap (47%), sfa (33%) e iha (4%); ibeA (29%); cnf1 (31%), hlyA (27%); fyuA (80%), iucD (22%); traT (51%); cvaC (20%) e malX (67%), cvaC (20%), and malX (67%). All feline strains were concentrated in B2 (89%) and D (11%) phylogenetic groups, whereas the canine ones were distributed in the four groups, A (5,5%), B1 (19,5%), B2 (55,5%) and D (19,5%). These findings suggesting that ExPEC isolated from dog and cat contain virulence markers to cause diseases, more severe than UTI, likewise in humans. Besides, these the close similarity between human and animal ExPEC supports the hypotesis of zoonotic potencial of them.

Chez la guêpe parasitoïde Venturia canescens, des particules virales dépourvues d'ADN appelées VLP (pour "Virus-like Particules") sont produites spécifiquement dans les ovaires et tapissent le chorion des oeufs qui sont injectés dans la chenille hôte. Les VLP ont une fonction immunosuppressive pour l'hôte parasité et permettent ainsi la survie des oeufs du parasitoïde. Ces VLP résultent de l’intégration d’un nudivirus dans le génome de l’ancêtre de la guêpe, nudivirus qui a été ensuite domestiqué pour former des liposomes viraux capables de véhiculer dans l’hôte des protéines de virulence d'origine cellulaire. L’étude réalisée au cours de cette thèse a eu pour objet, d’une part, d'étudier les mécanismes de domestication virale qui ont conduit au virus symbiotique endogène actuel nommé VcENV (pour V. canescens endogenous nudivirus) et d’autre part, d'apporter des éléments de réponse sur le processus de morphogénèse et le mode d'action parasitaire des VLP. / Viral particles devoid of DNA called VLPs (for Virus-Like Particles) are specifically produced in the ovaries of the parasitoid wasp Venturia canescens and line the chorion of the wasp’s eggs injected into the host caterpillar. VLPs are immunosuppressive and allow parasitoid eggs survival. These VLPs result from the integration of a nudivirus into the wasp ancestor genome, nudivirus which was then domesticated to form viral liposomes capable of carrying, into the host, virulence proteins of cellular origin. The aim of the study carried out during this thesis was, first, to analyze the viral domestication mechanisms that led to the current endogenous symbiotic virus called VcENV (for V. canescens endogenous nudivirus) and secondly to provide some answers on VLPs morphogenesis process and parasitic mode of action.