Candida albicans V132 induces trained immunity and enhances the responses triggered by the polybacterial vaccine MV140 for genitourinary tract infections

Abstract

IntroductionRecurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems all over the world. Antibiotics and antifungals are widely used for such infectious diseases, which is linked with microbial resistances and microbiota deleterious effects. The development of novel approaches for genitourinary tract infections (GUTIs) such as trained immunity-based vaccines (TIbV) is therefore highly required. MV140 is a sublingual whole-cell heat-inactivated polybacterial preparation with demonstrated clinical efficacy for RUTIs. The sublingual heat-inactivated Candida albicans vaccine V132 has been developed for RVVCs. We previously showed that the combination of MV140 and V132 promotes potent Th1/Th17 and regulatory T-cell responses against antigens contained in the formulation and unrelated antigens. The specific contribution of each preparation to such effects and the underlying molecular mechanisms remain incompletely understood.MethodsPBMC and monocytes were isolated from healthy donors and in vitro stimulated with V132, MV140 or MV140/V132. After 6 days of resting, cells were reestimulated with LPS and MV140. Analysis of cytokine production by ELISA, Seahorse assays for functional metabolic experiments and chromatin immunoprecipitation assays were performed. BALB/c mice were intraperitoneally and sublingually immunized with V132.ResultsWe uncover that V132 induces trained immunity in human PBMCs and purified monocytes, significantly increasing the responses triggered by subsequent stimulation with MV140. Mechanistically, V132 drives metabolic rewiring towards increased glycolysis and oxidative phosphorylation and induces epigenetic reprogramming that enhances the transcription of the pro-inflammatory genes IL6 and TNFA. Splenocytes and peritoneal cells from V132-immunize mice show increased responses upon in vitro stimulation with MV140. Remarkably, splenocytes from sublingually V132-immunized and MV140 in vivo treatment mice show stronger Th17 responses than mice exposed to excipients upon in vitro stimulation with MV140.ConclusionOverall, we provide novel mechanistic insights into how V132-induced trained immunity enhances both innate and adaptive immune responses triggered by MV140, which might open the door for new interventions for GUTIs with important clinical implications.

MV140 mucosal bacterial vaccine improves uropathogenic E. coli clearance in an experimental model of urinary tract infection

“…The rapid T cell response after infection clearly points to a prior induction due to vaccination with MV140. This is supported by previous works (5,6,15) and the present study, which show the induction of a systemic T-cell response in mice immunized with MV140. Notably, the extent of Th1/Th17 responses were very similar against E. coli strains V121 or UTI89, the latter not included in the formulation of MV140.…”

“…Such down-regulation was previously noted when analyzing in vitro the T cell-polarizing properties of human monocyte-derived DCs primed with MV140 (5,6). Th1 immunity induced in MV140-immunized mice, together with the IL-10 response (5,6,15), may also be involved in down-regulating established Th2 responses in vivo (16).…”

“…MV140 is a mucosal vaccine that has been shown to prevent UTI recurrences in different clinical settings (4,(12)(13)(14) including a randomized placebo-controlled clinical trial (4,(12)(13)(14). Preclinical studies, both in vitro and in vivo, indicate that MV140 is a potent activator of DCs, endorsing these cells the ability to induce Th1, Th17 and regulatory T (Treg) cells (5,6,15). However, direct evidence of MV140 conferring protection in an experimental UTI infection model was lacking.…”

Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation

“…For example, the presence of stimuli such as dexamethasone (Dex), vitamin D3 (VitD3), rapamycin, or allergoid-mannan conjugates promotes the differentiation of monocytes into tolerogenic DCs or immunosuppressive macrophages ( 22 – 26 ). Conversely, monocytes exposed with whole heat-inactivated Candida albicans or β-glucans from its cell wall give raise to trained monocyte-derived macrophages ( 27 – 29 ). Here, we show that LPS-stimulated WIN-hmoDCs displayed reduced production of the pro-inflammatory cytokines TNFα, IL-1β and IL-6 without changes in IL-10.…”

An Effective Sublingual Vaccine, MV140, Safely Reduces Risk of Recurrent Urinary Tract Infection in Women

“…Only recently have we gained some understanding of the mechanisms of action of most of these vaccines to induce protective immunity in the bladder that mediates this protection [ 20 , 21 , 22 ]. Mechanistic studies have shown that sublingual MV140 induces antibody production [ 23 ] and activates human dendritic cells to generate T helper (Th) 1, Th17, and interleukin-10, producing anti-inflammatory T-cell responses in secondary lymphoid organs and locally in the bladder [ 24 ]. The induction of adaptive immunity likely underlies the clinical protection observed following treatment discontinuation, although trained immunity (activation of the innate immune cells may result in enhanced responsiveness to subsequent bacterial triggers) could also play a role [ 23 , 25 ].…”