Sacramento Laís Amorim, Lombana Claudia, Scott Phillip
bioRxiv. 2024 Jun 9:2024.06.06.597776. doi: 10.1101/2024.06.06.597776.
Protein-energy malnutrition (PEM) is a risk factor for developing visceral leishmaniasis (VL). However, the impact on adaptive immunity during infection is unknown. To study the effect of malnutrition on chronic VL, we used a polynutrient-deficient diet (deficient protein, energy, zinc, and iron), which mimics moderate human malnutrition, followed by infection. The polynutrient-deficient diet leads to growth stunting and reduced mass of visceral organs. Malnourished-infected mice harbored more parasites in the spleen and liver, had a reduced number of T lymphocytes, reduced production of IFN-γ by T cells, and exhibited enhanced IL-10 production. To test whether IL-10 blockade would lessen disease in the malnourished mice, we treated infected mice with monoclonal antibody α-IL-10R. α-IL-10R treatment reduced the parasite number of malnourished mice, restored the number of T cells producing IFN-γ, and enhanced hepatic granuloma formation. Our results indicate that malnutrition increases VL susceptibility due to a defective IFN-γ-mediated immunity attributable to increased IL-10 production.
Malnutrition contributes to the development of VL. Despite the advances regarding this association, how malnutrition affects the adaptive immune mechanisms in VL is still unclear. We found that malnutrition disrupts the ability to control parasite replication in the spleen and liver in VL due to defective IFN-γ-mediated immunity, reduced hepatic granuloma formation, and enhanced IL-10 production. Blocking IL-10R signaling restored the protective mechanisms to control parasite replication in the malnourished mice without interfering with the undernutrition state. Thus, we demonstrate that malnutrition disrupts the adaptive immunity against VL due to an aberrant IL-10 production. Understanding the association between malnutrition and VL will provide insights into therapeutic approaches.
蛋白质能量营养不良（PEM）是内脏利什曼病（VL）发病的一个风险因素。然而，其在感染期间对适应性免疫的影响尚不清楚。为了研究营养不良对慢性VL的影响，我们采用了一种多营养素缺乏饮食（蛋白质、能量、锌和铁缺乏），这种饮食模拟了人类的中度营养不良，然后进行感染。多营养素缺乏饮食导致生长发育迟缓以及内脏器官重量减轻。营养不良且受感染的小鼠在脾脏和肝脏中寄生的寄生虫更多，T淋巴细胞数量减少，T细胞产生的干扰素-γ减少，并且白细胞介素-10的产生增加。为了测试阻断白细胞介素-10是否会减轻营养不良小鼠的疾病，我们用单克隆抗体α-IL-10R治疗受感染的小鼠。α-IL-10R治疗减少了营养不良小鼠的寄生虫数量，恢复了产生干扰素-γ的T细胞数量，并增强了肝脏肉芽肿的形成。我们的结果表明，营养不良会增加VL易感性，这是由于白细胞介素-10产生增加导致干扰素-γ介导的免疫功能缺陷所致。
营养不良会导致VL的发生。尽管在这一关联方面取得了进展，但营养不良如何影响VL中的适应性免疫机制仍不清楚。我们发现，由于干扰素-γ介导的免疫功能缺陷、肝脏肉芽肿形成减少以及白细胞介素-10产生增加，营养不良会破坏控制VL中脾脏和肝脏寄生虫复制的能力。阻断白细胞介素-10R信号通路可恢复营养不良小鼠控制寄生虫复制的保护机制，而不会干扰营养不足状态。因此，我们证明营养不良会因白细胞介素-10产生异常而破坏针对VL的适应性免疫。了解营养不良与VL之间的关联将为治疗方法提供见解。
