Abstract
Recurrent respiratory tract infections (RRTIs) are the first leading cause of community‐ and nosocomial‐acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat‐inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor‐interacting serine/threonine‐protein kinase‐2 (RIPK2)‐ and myeloid‐differentiation primary‐response gene‐88 (MyD88)‐mediated signalling pathways under the control of IL‐10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL‐10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.
Highlights
Patients suffering from recurrent respiratory tract infections (RRTIs) pose a major health-care problem with significant morbidity and mortality affecting both children and adults, representing an important economic burden in Europe and USA [1,2,3,4]
To assess the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs), we generated human monocyte-derived DCs from healthy subjects and RRTIs patients and compared the cytokine signature imprinted by this polybacterial preparations (PBP)
We combined systems biology and functional immunological approaches to demonstrate that MV130, a sublingual PBP to treat and prevent RRTIs, imprints human DCs with the capacity to generate Th1, Th17 and IL-10-producing T cells via receptor-interacting serine/threonine-protein kinase2 (RIPK2)- and myeloid-differentiation primary-response gene-88 (MyD88)-mediated signalling pathways under the control of IL-10
Summary
Patients suffering from recurrent respiratory tract infections (RRTIs) pose a major health-care problem with significant morbidity and mortality affecting both children and adults, representing an important economic burden in Europe and USA [1,2,3,4]. Clinical data showed that MV130 significantly reduced the rate of infections in RRTIs patients, the immunological ways of action remain elusive [3, 4, 14] Both specific and nonspecific mechanisms might well be involved in the observed clinical benefits [3, 15,16,17]. Our results provide novel insights into the immunomodulatory capacity of MV130 on human DCs as a potential mechanism that in cooperation with antigen-specific responses might well contribute to the reported clinical benefits in patients suffering from RRTIs. This study uncovers that the employed methodology constitutes a suitable strategy to elucidate immunological pathways activated by specific PBPs at the molecular level, which might well pave the way to develop more rational patient-tailored treatments for many other clinical conditions at high risk of recurrent infections
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