2026-07-21T08:17:02Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/190982024-10-31T11:57:54Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609
Repisalud
author
Bernardo, Lorena
author
Ibarra-Meneses, Ana Victoria
author
Douanne, Noelie
author
Corbeil, Audrey
author
Solana, Jose Carlos
author
Beaudry, Francis
author
Carrillo, Eugenia
author
Moreno, Javier
author
Fernandez-Prada, Christopher
funder
Natural Sciences and Engineering Research Council (Canada)
funder
Canada Foundation for Innovation
funder
Instituto de Salud Carlos III
funder
Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
2024-04-01T11:42:37Z
2024-04-01T11:42:37Z
2024-02
PLoS Negl Trop Dis. 2024 Feb 29;18(2):e0012015.
10.1371/journal.pntd.0012015
1935-2735
PLoS neglected tropical diseases
38422164
http://hdl.handle.net/20.500.12105/19098
Background: Visceral leishmaniasis (VL) resolution depends on a wide range of factors, including the instauration of an effective treatment coupled to a functional host immune system. Patients with a depressed immune system, like the ones receiving methotrexate (MTX), are at higher risk of developing VL and refusing antileishmanial drugs. Moreover, the alarmingly growing levels of antimicrobial resistance, especially in endemic areas, contribute to the increasing the burden of this complex zoonotic disease. Principal findings: To understand the potential links between immunosuppressants and antileishmanial drugs, we have studied the interaction of antimony (Sb) and MTX in a Leishmania infantum reference strain (LiWT) and in two L. infantum clinical strains (LiFS-A and LiFS-B) naturally circulating in non-treated VL dogs in Spain. The LiFS-A strain was isolated before Sb treatment in a case that responded positively to the treatment, while the LiFS-B strain was recovered from a dog before Sb treatment, with the dog later relapsing after the treatment. Our results show that, exposure to Sb or MTX leads to an increase in the production of reactive oxygen species (ROS) in LiWT which correlates with a sensitive phenotype against both drugs in promastigotes and intracellular amastigotes. LiFS-A was sensitive against Sb but resistant against MTX, displaying high levels of protection against ROS when exposed to MTX. LiFS-B was resistant to both drugs. Evaluation of the melting proteomes of the two LiFS, in the presence and absence of Sb and MTX, showed a differential enrichment of direct and indirect targets for both drugs, including common and unique pathways. Conclusion: Our results show the potential selection of Sb-MTX cross-resistant parasites in the field, pointing to the possibility to undermine antileishmanial treatment of those patients being treated with immunosuppressant drugs in Leishmania endemic areas.
eng
Potential selection of antimony and methotrexate cross-resistance in Leishmania infantum circulating strains
research article
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