title: MV140, a sublingual polyvalent bacterial preparation to treat recurrent urinary tract infections, licenses human dendritic cells for generating Th1, Th17, and IL-10 responses via Syk and MyD88.
abstract: Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown. Herein, we demonstrated that MV140 endorses human dendritic cells (DCs) with the capacity to generate Th1/Th17 and IL-10-producing T cells by mechanisms depending on spleen tyrosine kinase (Syk)- and myeloid differentiation primary response gene 88 (MyD88)-mediated pathways. MV140-induced activation of nuclear factor κB (NF-κB) and p38 in human DCs is essential for the generated Th1/Th17 and IL-10 immune responses whereas c-Jun N-terminal Kinase (JNK) and extracellular-signal regulated kinase (ERK) contribute to Th1 and IL-10 responses, respectively. Sublingual immunization of BALB/c mice with MV140 also induces potent systemic Th1/Th17 and IL-10 responses in vivo. We uncover immunological mechanisms underlying the way of action of MV140, which might well also contribute to understand the rational use of specific PBPs in other clinical conditions with potential high risk of recurrent infections.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Benito-Villalvilla
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Cirauqui
authors.affiliation: Inmunotek, SL. Alcalá de Henares, Madrid, Spain.
authors.forename: C M
authors.initials: CM
authors.lastname: Diez-Rivero
authors.affiliation: Inmunotek, SL. Alcalá de Henares, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Casanovas
authors.affiliation: Inmunotek, SL. Alcalá de Henares, Madrid, Spain.|Department of Immunology, Hospital Clínico San Carlos and School of Medicine, Complutense University of Madrid, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Subiza
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Palomares
mesh_terms: D000286:Administration, Sublingual; D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016753:Interleukin-10 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014552:Urinary Tract Infections / Q000276:immunology* / Q000517:prevention & control
chemical_list: D001428:Bacterial Vaccines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C581747:uromune; D016753:Interleukin-10; D000072377:Syk Kinase