The different impact of drug-resistant Leishmania on the transcription programs activated in neutrophils
Míriam Díaz-Varela,
Andrea Sanchez-Hidalgo,
Sandra Calderon-Copete,
Virginie Tacchini,
Tobias R. Shipley,
Lady Giovanna Ramírez,
Julien Marquis,
Olga Lucía Fernández,
Nancy Gore Saravia,
Fabienne Tacchini-Cottier
Affiliations
Míriam Díaz-Varela
Department of Immunobiology, WHO Collaborative Center for Research and Training in Immunology, University of Lausanne, 1066 Epalinges, Switzerland; Corresponding author
Andrea Sanchez-Hidalgo
Centro Internacional de Entrenamiento e Investigaciones Médicas, CIDEIM, Cali 760031, Colombia; Universidad Icesi, Cali 760031, Colombia
Sandra Calderon-Copete
Lausanne Genomic Technologies Facility, University of Lausanne, 1015 Lausanne, Switzerland
Virginie Tacchini
Department of Immunobiology, WHO Collaborative Center for Research and Training in Immunology, University of Lausanne, 1066 Epalinges, Switzerland
Tobias R. Shipley
Department of Immunobiology, WHO Collaborative Center for Research and Training in Immunology, University of Lausanne, 1066 Epalinges, Switzerland
Lady Giovanna Ramírez
Centro Internacional de Entrenamiento e Investigaciones Médicas, CIDEIM, Cali 760031, Colombia; Universidad Icesi, Cali 760031, Colombia
Julien Marquis
Lausanne Genomic Technologies Facility, University of Lausanne, 1015 Lausanne, Switzerland
Olga Lucía Fernández
Centro Internacional de Entrenamiento e Investigaciones Médicas, CIDEIM, Cali 760031, Colombia; Universidad Icesi, Cali 760031, Colombia
Nancy Gore Saravia
Centro Internacional de Entrenamiento e Investigaciones Médicas, CIDEIM, Cali 760031, Colombia; Universidad Icesi, Cali 760031, Colombia
Fabienne Tacchini-Cottier
Department of Immunobiology, WHO Collaborative Center for Research and Training in Immunology, University of Lausanne, 1066 Epalinges, Switzerland; Corresponding author
Summary: 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 Leishmania 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.
