Abstract
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-γ– and IL-17A–producing T cells and FOXP3+ regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- 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.
Highlights
Bacterial infections represent a major health-care problem and among them, urinary tract infections (UTIs) are one of the most common with a high incidence in women [1,2,3,4]
We demonstrated that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to generate potent IFN-g– and IL-17A–producing T cells and FOXP3+ regulatory T (Treg) cells
To test whether simultaneous stimulation of human monocyte-derived DCs (hmoDCs) with MV140/V132 enhance the production of TNF-a, IL-23, and IL-10 in a synergistic manner, cytokine levels induced by MV140/V132 showed in Figure 1A were directly compared to those resulting from the addition of the cytokine levels produced by activation with MV140 and V132 separately (Figure 1A)
Summary
Bacterial infections represent a major health-care problem and among them, urinary tract infections (UTIs) are one of the most common with a high incidence in women [1,2,3,4]. More than 70% of women worldwide suffer from VVCs (with maximum incidence between 20 and 40 years old) and around 5% experience recurrent infections (RVVCs), defined as four or more episodes per year [13,14,15,16]. RVVCs require antifungal therapy to avoid recurrence and its overuse involves antimycotic resistances [17,18,19]. Both RUTIs and RVVCs markedly diminish quality of life in women, with a negative impact at work and social life [20, 21]. There is an urgent need to develop novel strategies for concomitant and recurrent genitourinary tract infections (GUTIs), including RUTIs and RVVCs [1, 4, 16,17,18, 22]
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