Díaz-Varela Míriam, Sanchez-Hidalgo Andrea, Calderon-Copete Sandra, Tacchini Virginie, Shipley Tobias R, Ramírez Lady Giovanna, Marquis Julien, Fernández Olga Lucía, Saravia Nancy Gore, Tacchini-Cottier Fabienne
Department of Immunobiology, WHO Collaborative Center for Research and Training in Immunology, University of Lausanne, 1066 Epalinges, Switzerland.
Centro Internacional de Entrenamiento e Investigaciones Médicas, CIDEIM, Cali 760031, Colombia.
iScience. 2024 Apr 18;27(5):109773. doi: 10.1016/j.isci.2024.109773. eCollection 2024 May 17.
Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control, but their role in drug-resistant infections is poorly understood. Here, we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that antimony drug resistance significantly altered the expression of neutrophil genes, some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these, the chemokine CCL3 was predominantly impacted, which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover, decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively, these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment, revealing a key role of neutrophils in drug resistance.
耐药性威胁着包括利什曼病等寄生虫病在内的感染性疾病的有效控制。中性粒细胞是抗菌防御的重要参与者，但其在耐药性感染中的作用却鲜为人知。在此，我们评估了人类中性粒细胞对具有不同天然药物敏感性的临床寄生虫菌株的反应。我们发现，锑耐药性显著改变了中性粒细胞基因的表达，其中一些基因由特定的中性粒细胞亚群转录。感染耐药寄生虫会增加解毒途径的表达并减少细胞因子的产生。其中，趋化因子CCL3受到的影响最为显著，这导致中性粒细胞吸引髓系细胞的能力受损。此外，通过在小鼠模型中阻断CCL3，证实了CCL3水平降低时髓系细胞募集减少。这些发现共同揭示，天然耐药寄生虫与中性粒细胞之间的相互作用调节了感染皮肤的免疫微环境，揭示了中性粒细胞在耐药性中的关键作用。
