Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo. Ribeirão Preto, Brazil.
Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo. Ribeirão Preto, Brazil.
PLoS Pathog. 2019 Sep 3;15(9):e1007934. doi: 10.1371/journal.ppat.1007934. eCollection 2019 Sep.
Mayaro virus (MAYV) is an arbovirus that circulates in Latin America and is emerging as a potential threat to public health. Infected individuals develop Mayaro fever, a severe inflammatory disease characterized by high fever, rash, arthralgia, myalgia and headache. The disease is often associated with a prolonged arthralgia mediated by a chronic inflammation that can last months. Although the immune response against other arboviruses, such as chikungunya virus (CHIKV), dengue virus (DENV) and Zika virus (ZIKV), has been extensively studied, little is known about the pathogenesis of MAYV infection. In this study, we established models of MAYV infection in macrophages and in mice and found that MAYV can replicate in bone marrow-derived macrophages and robustly induce expression of inflammasome proteins, such as NLRP3, ASC, AIM2, and Caspase-1 (CASP1). Infection performed in macrophages derived from Nlrp3-/-, Aim2-/-, Asc-/-and Casp1/11-/-mice indicate that the NLRP3, but not AIM2 inflammasome is essential for production of inflammatory cytokines, such as IL-1β. We also determined that MAYV triggers NLRP3 inflammasome activation by inducing reactive oxygen species (ROS) and potassium efflux. In vivo infections performed in inflammasome-deficient mice indicate that NLRP3 is involved with footpad swelling, inflammation and pain, establishing a role of the NLRP3 inflammasome in the MAYV pathogenesis. Accordingly, we detected higher levels of caspase1-p20, IL-1β and IL-18 in the serum of MAYV-infected patients as compared to healthy individuals, supporting the participation of the NLRP3-inflammasome during MAYV infection in humans.
马亚罗病毒（MAYV）是一种虫媒病毒，在拉丁美洲流行，正逐渐成为公共卫生的潜在威胁。感染该病毒的个体患马亚罗热，这是一种严重的炎症性疾病，其特征为高热、皮疹、关节炎、肌痛和头痛。该疾病常伴有由慢性炎症介导的长期关节痛，可持续数月。尽管针对其他虫媒病毒（如基孔肯雅病毒（CHIKV）、登革热病毒（DENV）和寨卡病毒（ZIKV））的免疫反应已被广泛研究，但对 MAYV 感染的发病机制知之甚少。在这项研究中，我们建立了 MAYV 在巨噬细胞和小鼠中的感染模型，发现 MAYV 可以在骨髓来源的巨噬细胞中复制，并强烈诱导炎症小体蛋白（如 NLRP3、ASC、AIM2 和 Caspase-1（CASP1））的表达。在 Nlrp3-/-、Aim2-/-、Asc-/-和 Casp1/11-/-小鼠来源的巨噬细胞中进行的感染表明，NLRP3 炎症小体而非 AIM2 炎症小体对于炎性细胞因子（如 IL-1β）的产生至关重要。我们还确定 MAYV 通过诱导活性氧（ROS）和钾外流来触发 NLRP3 炎症小体的激活。在炎症小体缺陷型小鼠的体内感染表明，NLRP3 参与足垫肿胀、炎症和疼痛，确立了 NLRP3 炎症小体在 MAYV 发病机制中的作用。因此，与健康个体相比，我们在感染 MAYV 的患者血清中检测到更高水平的 caspase1-p20、IL-1β和 IL-18，支持 NLRP3 炎症小体在人类 MAYV 感染过程中的参与。
