Cardoso Flávia de Oliveira, Zaverucha-do-Valle Tânia, Almeida-Souza Fernando, Abreu-Silva Ana Lúcia, Calabrese Kátia da Silva
Laboratório de Imunomodulação e Protozoologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Laboratório de Anatomopatologia, Departamento de Patologia, Universidade Estadual do Maranhão, São Luís, Brazil.
Front Microbiol. 2020 Aug 31;11:1986. doi: 10.3389/fmicb.2020.01986. eCollection 2020.
Leishmaniases are a complex of diseases with a broad spectrum of clinical forms, which depend on the parasite species, immunological status, and genetic background of the host. In the model, susceptibility is associated with the Th2 pattern of cytokines production, while resistance is associated with Th1 response. However, the same dichotomy does not occur in -infected mice. Cytokines are key players in these diseases progression, while the extracellular matrix (ECM) components participate in the process of parasite invasion as well as lesion healing. In this article, we analyzed the influence of host genetics on the expression of cytokines, inducible nitric oxide synthase (iNOS), and ECM proteins, as well as the parasite load in mice with different genetic backgrounds infected by . C57BL/10 and C3H/He mice were subcutaneously infected with 10 promastigotes. Lesion kinetics, parasite load, cytokines, iNOS, and ECM proteins expression were measured by quantitative PCR (qPCR) in the footpad, draining lymph nodes, liver, and spleen at early (24 h and 30 days) and late phase (120 and 180 days) of infection. Analysis of lesion kinetics showed that C57BL/10 mice developed ulcerative lesions at the inoculation site after infection, while C3H/He showed slight swelling in the footpad 180 days after infection. C57BL/10 showed progressive enhancement of parasite load in all analyzed organs, while C3H/He mice showed extremely low parasite loads. Susceptible C57BL/10 mice showed high levels of TGF-β mRNA in the footpad early in infection and high levels of proinflammatory cytokines mRNA (IL-12, TNF-α, and IFN-γ) and iNOS in the late phase of the infection. There is an association between increased expression of fibronectin, laminin, collagen III and IV, and TGF-β. On the other hand, resistant C3H/He mice presented a lower repertory of cytokines mRNA expression when compared with susceptible C57BL/10 mice, basically producing TNF-α, collagen IV, and laminin early in infection. The findings of our study indicate that infection induces different cytokine expression in resistant and susceptible mice but not like the model. An organ-compartmentalized cytokine response was observed in our model. Host genetics determine this response, which modulates ECM proteins expression.
利什曼病是一组具有广泛临床形式的疾病，其取决于寄生虫种类、宿主的免疫状态和遗传背景。在该模型中，易感性与细胞因子产生的Th2模式相关，而抗性与Th1反应相关。然而，在感染的小鼠中并未出现同样的二分法。细胞因子是这些疾病进展的关键因素，而细胞外基质（ECM）成分参与寄生虫入侵以及损伤愈合过程。在本文中，我们分析了宿主遗传学对细胞因子、诱导型一氧化氮合酶（iNOS）和ECM蛋白表达的影响，以及不同遗传背景的小鼠感染后寄生虫载量的影响。C57BL/10和C3H/He小鼠皮下接种10个前鞭毛体。在感染的早期（24小时和30天）和晚期（120天和180天），通过定量PCR（qPCR）测量足垫、引流淋巴结、肝脏和脾脏中的病变动力学、寄生虫载量、细胞因子、iNOS和ECM蛋白表达。病变动力学分析表明，C57BL/10小鼠感染后在接种部位出现溃疡性病变，而C3H/He小鼠在感染180天后足垫出现轻微肿胀。C57BL/10在所有分析器官中的寄生虫载量呈逐渐增加趋势，而C3H/He小鼠的寄生虫载量极低。易感的C57BL/10小鼠在感染早期足垫中TGF-β mRNA水平较高，在感染后期促炎细胞因子mRNA（IL-12、TNF-α和IFN-γ）和iNOS水平较高。纤连蛋白、层粘连蛋白、胶原蛋白III和IV的表达增加与TGF-β之间存在关联。另一方面，抗性的C3H/He小鼠与易感的C57BL/10小鼠相比，细胞因子mRNA表达谱较低，在感染早期主要产生TNF-α、胶原蛋白IV和层粘连蛋白。我们的研究结果表明，感染在抗性和易感小鼠中诱导不同的细胞因子表达，但与模型不同。在我们的模型中观察到了器官分区化的细胞因子反应。宿主遗传学决定了这种反应，该反应调节ECM蛋白表达。
