000151022 001__ 151022
000151022 005__ 20251017144623.0
000151022 0247_ $$2doi$$a10.1016/j.omtn.2022.02.011
000151022 0248_ $$2sideral$$a128404
000151022 037__ $$aART-2022-128404
000151022 041__ $$aeng
000151022 100__ $$0(orcid)0000-0001-5407-7271$$aPérez, Irene
000151022 245__ $$aThe Mycobacterium tuberculosis PhoPR virulence system regulates expression of the universal second messenger c-di-AMP and impacts vaccine safety and efficacy
000151022 260__ $$c2022
000151022 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151022 5203_ $$aCyclic (di)nucleotides act as universal second messengers endogenously produced by several pathogens. Specifically, the roles of c-di-AMP in Mycobacterium tuberculosis immunity and virulence have been largely explored, although its contribution to the safety and efficacy of live tuberculosis vaccines is less understood. In this study, we demonstrate that the synthesis of c-di-AMP is negatively regulated by the M. tuberculosis PhoPR virulence system. Accordingly, the live attenuated tuberculosis vaccine candidate M. tuberculosis vaccine (MTBVAC), based on double phoP and fadD26 deletions, produces more than 25- and 45-fold c-di-AMP levels relative to wild-type M. tuberculosis or the current vaccine bacille Calmette-Guérin (BCG), respectively. Secretion of this second messenger was exclusively detected in MTBVAC but not in M. tuberculosis or in BCG. We also demonstrate that c-di-AMP synthesis during in vitro cultivation of M. tuberculosis is a growth-phase- and medium-dependent phenotype. To uncover the role of this metabolite in the vaccine properties of MTBVAC, we constructed and validated knockout and overproducing/oversecreting derivatives by inactivating the disA or cnpB gene, respectively. All MTBVAC derivatives elicited superior interleukin-1ß (IL-1ß) responses compared with BCG during an in vitro infection of human macrophages. However, both vaccines failed to elicit interferon ß (IFNß) activation in this cellular model. We found that increasing c-di-AMP levels remarkably correlated with a safer profile of tuberculosis vaccines in the immunodeficient mouse model. Finally, we demonstrate that overproduction of c-di-AMP due to cnpB inactivation resulted in lower protection of MTBVAC, while the absence of c-di-AMP in the MTBVAC disA derivative maintains the protective efficacy of this vaccine in mice.
000151022 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-104690RB-I00$$9info:eu-repo/grantAgreement/ES/UZ-IBERCAJA-CAI/CM3-18
000151022 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
000151022 590__ $$a8.8$$b2022
000151022 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b18 / 136 = 0.132$$c2022$$dQ1$$eT1
000151022 592__ $$a1.947$$b2022
000151022 593__ $$aMolecular Medicine$$c2022$$dQ1
000151022 593__ $$aDrug Discovery$$c2022$$dQ1
000151022 594__ $$a15.6$$b2022
000151022 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151022 700__ $$aCampos-Pardos, Elena$$uUniversidad de Zaragoza
000151022 700__ $$aDíaz, Caridad
000151022 700__ $$0(orcid)0000-0001-7866-2803$$aUranga, Santiago$$uUniversidad de Zaragoza
000151022 700__ $$aSayes, Fadel
000151022 700__ $$aVicente, Francisca
000151022 700__ $$0(orcid)0000-0001-7897-9173$$aAguiló, Nacho$$uUniversidad de Zaragoza
000151022 700__ $$aBrosch, Roland
000151022 700__ $$0(orcid)0000-0003-2993-5478$$aMartín, Carlos$$uUniversidad de Zaragoza
000151022 700__ $$0(orcid)0000-0001-8841-6593$$aGonzalo-Asensio , Jesús$$uUniversidad de Zaragoza
000151022 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000151022 7102_ $$11011$$2X$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cProy. investigación HQA
000151022 773__ $$g27 (2022), 1235-1248$$pMol. ther., Nucleic acids$$tMolecular therapy. Nucleic acids$$x2162-2531
000151022 8564_ $$s1930485$$uhttps://zaguan.unizar.es/record/151022/files/texto_completo.pdf$$yVersión publicada
000151022 8564_ $$s3122486$$uhttps://zaguan.unizar.es/record/151022/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151022 909CO $$ooai:zaguan.unizar.es:151022$$particulos$$pdriver
000151022 951__ $$a2025-10-17-14:22:30
000151022 980__ $$aARTICLE