PMID- 33552074 OWN - NLM STAT- MEDLINE DCOM- 20210622 LR - 20240330 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - A Combination of Polybacterial MV140 and Candida albicans V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections. PG - 612269 LID - 10.3389/fimmu.2020.612269 [doi] LID - 612269 AB - Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated Candida albicans developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-gamma- and IL-17A-producing T cells and FOXP3(+) regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-kappaB (NF-kappaB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4(+) T cells not only upon in vitro stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, in vivo sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs. CI - Copyright (c) 2021 Martin-Cruz, Sevilla-Ortega, Benito-Villalvilla, Diez-Rivero, Sanchez-Ramon, Subiza and Palomares. FAU - Martin-Cruz, Leticia AU - Martin-Cruz L AD - Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain. FAU - Sevilla-Ortega, Carmen AU - Sevilla-Ortega C AD - Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain. FAU - Benito-Villalvilla, Cristina AU - Benito-Villalvilla C AD - Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain. FAU - Diez-Rivero, Carmen M AU - Diez-Rivero CM AD - Inmunotek, Alcala de Henares, Madrid, Spain. FAU - Sanchez-Ramon, Silvia AU - Sanchez-Ramon S AD - Department of Clinical Immunology and IdISSC, Hospital Clinico San Carlos, Madrid, Spain. AD - Department of Immunology, ENT and Ophthalmology, School of Medicine, Complutense University, Madrid, Spain. FAU - Subiza, Jose Luis AU - Subiza JL AD - Inmunotek, Alcala de Henares, Madrid, Spain. FAU - Palomares, Oscar AU - Palomares O AD - Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210121 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, Bacterial) RN - 0 (Antigens, Fungal) RN - 0 (Bacterial Vaccines) RN - 0 (Cytokines) RN - 0 (Fungal Vaccines) RN - 0 (Vaccines, Combined) SB - IM MH - Animals MH - Antigens, Bacterial/*administration & dosage/immunology MH - Antigens, Fungal/*administration & dosage/immunology MH - Bacterial Infections/immunology/metabolism/microbiology/*prevention & control MH - Bacterial Vaccines/*administration & dosage/immunology MH - CD4-Positive T-Lymphocytes/drug effects/immunology MH - Candidiasis, Vulvovaginal/immunology/metabolism/microbiology/*therapy MH - Cells, Cultured MH - Coculture Techniques MH - Cytokines/metabolism MH - Dendritic Cells/drug effects/immunology MH - Female MH - Fungal Vaccines/*administration & dosage/immunology MH - Humans MH - Lymphocyte Activation/drug effects MH - Mice, Inbred BALB C MH - Phenotype MH - Urinary Tract Infections/immunology/metabolism/microbiology/*prevention & control MH - Vaccination MH - Vaccines, Combined/*administration & dosage/immunology MH - Mice PMC - PMC7858650 OTO - NOTNLM OT - candida albicans V132 OT - dendritic cells OT - polybacterial preparation MV140 OT - recurrent urinary tract infections (RUTIs) OT - recurrent vulvovaginal candidiasis (RVVCs) OT - trained immunity-based vaccines (TIbVs) COIS- OP has received fee for lectures or participation in Advisory Boards from Allergy Therapeutics, Amgen, AstraZeneca, Diater, GSK, Inmunotek SL, Novartis, Sanofi Genzyme, Stallergenes and Regeneron. OP has received research grants from Inmunotek SL and Novartis SL. JS is the founder and CEO of Inmunotek SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SI declared a shared affiliation, with no collaboration, with several of the authors, LC, CO, CV and OP, to the handling editor at the time of review. EDAT- 2021/02/09 06:00 MHDA- 2021/06/23 06:00 PMCR- 2020/01/01 CRDT- 2021/02/08 05:36 PHST- 2020/09/30 00:00 [received] PHST- 2020/12/03 00:00 [accepted] PHST- 2021/02/08 05:36 [entrez] PHST- 2021/02/09 06:00 [pubmed] PHST- 2021/06/23 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.612269 [doi] PST - epublish SO - Front Immunol. 2021 Jan 21;11:612269. doi: 10.3389/fimmu.2020.612269. eCollection 2020.