3′Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine

Carnielli, Juliana B.T.; Dave, Anuja; Romano, Antonino; Forrester, Sarah; Faria, Pedro Rosseto de; Monti-Rocha, Renata; Costa, Carlos Henrique Nery; Dietze, Reynaldo; Graham, Ian A.; Mottram, Jeremy C.

doi:10.1016/j.ebiom.2022.104378

Cited by 8 publications

(2 citation statements)

References 63 publications

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“…Moreover, it is implicated as a virulence factor affecting the parasite's ability to infect macrophages [9][10][11] and survive neutrophil extracellular traps (NETs) 12,13 . Recent evidence has linked 3'NU/NT to susceptibility to miltefosine (MIL) 14 , a critical drug in leishmaniasis treatment, and clinical trials have shown a correlation between reduced MIL efficacy in AVL treatment and infection by DEL strains 15 . Despite this, MIL is approved to be utilized in the treatment of canine visceral leishmaniasis (CVL), prompting concerns regarding surveillance and control 16 .…”

Section: Introductionmentioning

confidence: 99%

Gene deletion as a possible strategy adopted by New WorldLeishmania infantumto maximize geographic dispersion

Florêncio,

Chagas,

Guimarães-Costa

et al. 2024

Preprint

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The present study investigates implications of a sub-chromosomal deletion in Leishmania infantum strains, the causative agent of American Visceral Leishmaniasis (AVL). Primarily found in New World strains, the deletion leads to the absence of the ecto-3-nucleotidase/nuclease enzyme (3NU/NT), impacting parasite virulence, pathogenicity, and drug susceptibility. The potential factors favoring prevalence and the widespread geographic distribution of these deleted mutant parasites (DEL) in the New World (NW) are discussed under the generated data. We conducted phenotypic analyses of the parasites showing the sub-chromosomal deletion by applying in vitro assays of 3NU/NT activity, metacyclic enrichment, and relative quantitation of transcripts abundance on axenic parasites. We further performed experimental infections in both in vitro and in vivo models of vertebrate and invertebrate hosts using geographically diverse mutant field isolates. Virulence assays, poorer ability to survive neutrophil traps (NETs) and murine model infection revealed reduced pathogenicity in vertebrate hosts by the DEL strains. Conversely, these parasites exhibit enhanced metacyclogenesis and colonization rates in sand flies, potentially facilitating transmission. This combination may represent a more efficient way to maintain and disperse the transmission cycle of DEL strains. Phenotypic assessments reveal altered parasite fitness, with enhanced transmissibility at the population level. Reduced susceptibility of DEL strains to miltefosine, a key drug in VL treatment, further complicates control efforts. Our study underscores the importance of typing parasite genomes for surveillance and control and proposes the sub-chromosomal deletion as a molecular marker in AVL management.

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Section: Introductionmentioning

confidence: 99%

Gene deletion as a possible strategy adopted by New WorldLeishmania infantumto maximize geographic dispersion

Florêncio,

Chagas,

Guimarães-Costa

et al. 2024

Preprint

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“…This genomic region contains four genes, 3′-nucleotidase/nucleases ( NUC1 and NUC2 ), helicase-like protein, and 3,2-trans-enoyl-CoA isomerase, and is known as the miltefosine sensitive locus (MSL) [ 11 , 12 ]. The absence of NUC1 and NUC2 genes was later shown to be specifically responsible for the reduction of MF susceptibility in parasites, due to a higher resistance to lipid metabolism perturbations caused by the drug [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Drug Susceptibility of a Leishmania (Leishmania) infantum Isolate from a Visceral Leishmaniasis Pediatric Patient after Multiple Relapses

et al. 2023

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The parasitic protozoan Leishmania (Leishmania) infantum is the etiological agent of human visceral leishmaniasis in South America, an infectious disease associated with malnutrition, anemia, and hepatosplenomegaly. In Brazil alone, around 2700 cases are reported each year. Treatment failure can occur as a result of drug, host, and/or parasite-related factors. Here, we isolated a Leishmania species from a pediatric patient with visceral leishmaniasis that did not respond to chemotherapy, experiencing a total of nine therapeutic relapses and undergoing a splenectomy. The parasite was confirmed as L. (L.) infantum after sequencing of the ribosomal DNA internal transcribed spacer, and the clinical isolate, in both promastigote and amastigote forms, was submitted to in vitro susceptibility assays with all the drugs currently used in the chemotherapy of leishmaniasis. The isolate was susceptible to meglumine antimoniate, amphotericin B, pentamidine, miltefosine, and paromomycin, similarly to another strain of this species that had previously been characterized. These findings indicate that the multiples relapses observed in this pediatric patient were not due to a decrease in the drug susceptibility of this isolate; therefore, immunophysiological aspects of the patient should be further investigated to understand the basis of treatment failure in this case.

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Miltefosine Unresponsiveness in Visceral Leishmaniasis

Singh,

Verma,

Ghosh

et al. 2023

Challenges and Solutions Against Visceral Leishmaniasis

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3′Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine

Cited by 8 publications

References 63 publications

Gene deletion as a possible strategy adopted by New WorldLeishmania infantumto maximize geographic dispersion

Gene deletion as a possible strategy adopted by New WorldLeishmania infantumto maximize geographic dispersion

In Vitro Drug Susceptibility of a Leishmania (Leishmania) infantum Isolate from a Visceral Leishmaniasis Pediatric Patient after Multiple Relapses

Miltefosine Unresponsiveness in Visceral Leishmaniasis

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