Bernardo Lorena, Montero-Calle Ana, Solana Jose Carlos, Lozano-Rendal Marina, Torres Ana, Sánchez Carmen, Barderas Rodrigo, Moreno Javier, Carrillo Eugenia
WHO Collaborating Centre for Leishmaniasis, Spanish National Center for Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
Front Immunol. 2025 Jul 30;16:1634080. doi: 10.3389/fimmu.2025.1634080. eCollection 2025.
Visceral leishmaniasis (VL) occurs more frequently in immunosuppressed individuals, especially those undergoing immunosuppressive drug therapy for an autoimmune disease. In those receiving TNF antagonist therapy (anti-TNF), the course of VL is more severe and the response to traditional leishmanicidal treatments, such as antimonials (Sb), is often reduced. This effect of anti-TNF treatment is observed in our immunosuppressed-mouse model of VL. In this model, we compared anti-TNF immunosuppression with no immunosuppression before and after VL treatment with Sb.
Serum-derived extracellular vesicles (EVs) were analyzed through label-free quantitative proteomics to identify proteins involved in both VL severity and the impact of anti-TNF immunosuppression on treatment outcome.
In total, 223 dysregulated proteins were found in the pre-treatment groups, the majority of which, such as vitronectin, haemopexin or caveolin-1, were downregulated in the anti-TNF samples. In contrast, 173 proteins were identified in the Sb-treatment groups, most of which were found enriched in the anti-TNF plus treatment samples (anti-TNF+Sb) including fibronectin, transferrin, vitronectin and dipeptidyl peptidase-4. These differentially-expressed proteins were associated with pathways related to the immune system, liver regeneration, and ion transport.
Our findings have useful implications for the clinical management of VL patients under anti-TNF immunosuppression.
内脏利什曼病（VL）在免疫抑制个体中更为常见，尤其是那些因自身免疫性疾病接受免疫抑制药物治疗的患者。在接受肿瘤坏死因子拮抗剂治疗（抗TNF）的患者中，VL病程更为严重，对传统抗利什曼原虫治疗（如锑剂）的反应通常降低。在我们的VL免疫抑制小鼠模型中观察到了抗TNF治疗的这种效果。在该模型中，我们比较了在用锑剂治疗VL前后抗TNF免疫抑制与非免疫抑制的情况。
通过无标记定量蛋白质组学分析血清来源的细胞外囊泡（EVs），以鉴定与VL严重程度以及抗TNF免疫抑制对治疗结果的影响相关的蛋白质。
在预处理组中共发现223种失调蛋白，其中大多数，如玻连蛋白、血红素结合蛋白或小窝蛋白-1，在抗TNF样本中表达下调。相比之下，在锑剂治疗组中鉴定出173种蛋白，其中大多数在抗TNF加治疗样本（抗TNF+Sb）中富集，包括纤连蛋白、转铁蛋白、玻连蛋白和二肽基肽酶-4。这些差异表达的蛋白与免疫系统、肝脏再生和离子转运相关的途径有关。
我们的研究结果对接受抗TNF免疫抑制的VL患者的临床管理具有重要意义。
