Arboleda Alzate John F, Rodenhuis-Zybert Izabela A, Hernández Juan C, Smit Jolanda M, Urcuqui-Inchima Silvio
Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia.
Department of Medical Microbiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
PLoS Negl Trop Dis. 2017 Oct 11;11(10):e0005904. doi: 10.1371/journal.pntd.0005904. eCollection 2017 Oct.
Severe dengue disease is associated with high viral loads and overproduction of pro-inflammatory cytokines, suggesting impairment in the control of dengue virus (DENV) and the mechanisms that regulate cytokine production. Vitamin D3 has been described as an important modulator of immune responses to several pathogens. Interestingly, increasing evidence has associated vitamin D with decreased DENV infection and early disease recovery, yet the molecular mechanisms whereby vitamin D reduces DENV infection are not well understood.
Macrophages represent important cell targets for DENV replication and consequently, they are key drivers of dengue disease. In this study we evaluated the effect of vitamin D3 on the differentiation of monocyte-derived macrophages (MDM) and their susceptibility and cytokine response to DENV. Our data demonstrate that MDM differentiated in the presence of vitamin D3 (D3-MDM) restrict DENV infection and moderate the classical inflammatory cytokine response. Mechanistically, vitamin D3-driven differentiation led to reduced surface expression of C-type lectins including the mannose receptor (MR, CD206) that is known to act as primary receptor for DENV attachment on macrophages and to trigger of immune signaling. Consequently, DENV bound less efficiently to vitamin D3-differentiated macrophages, leading to lower infection. Interestingly, IL-4 enhanced infection was reduced in D3-MDM by restriction of MR expression. Moreover, we detected moderate secretion of TNF-α, IL-1β, and IL-10 in D3-MDM, likely due to less MR engagement during DENV infection.
CONCLUSIONS/SIGNIFICANCE: Our findings reveal a molecular mechanism by which vitamin D counteracts DENV infection and progression of severe disease, and indicates its potential relevance as a preventive or therapeutic candidate.
严重登革热疾病与高病毒载量及促炎细胞因子的过度产生有关，这表明登革病毒（DENV）的控制以及调节细胞因子产生的机制存在缺陷。维生素D3已被描述为对多种病原体免疫反应的重要调节剂。有趣的是，越来越多的证据表明维生素D与降低DENV感染及早期疾病恢复有关，然而维生素D降低DENV感染的分子机制尚不清楚。
巨噬细胞是DENV复制的重要细胞靶点，因此是登革热疾病的关键驱动因素。在本研究中，我们评估了维生素D3对单核细胞衍生巨噬细胞（MDM）分化及其对DENV的易感性和细胞因子反应的影响。我们的数据表明，在维生素D3存在下分化的MDM（D3-MDM）可限制DENV感染并调节经典炎症细胞因子反应。从机制上讲，维生素D3驱动的分化导致C型凝集素的表面表达减少，包括甘露糖受体（MR，CD206），已知该受体是DENV在巨噬细胞上附着的主要受体并触发免疫信号。因此，DENV与维生素D3分化的巨噬细胞结合效率较低，导致感染率降低。有趣的是，通过限制MR表达，D3-MDM中IL-4增强的感染减少。此外，我们检测到D3-MDM中TNF-α、IL-1β和IL-10的分泌适度，这可能是由于DENV感染期间MR参与较少。
结论/意义：我们的研究结果揭示了维生素D对抗DENV感染和严重疾病进展的分子机制，并表明其作为预防或治疗候选药物的潜在相关性。
