Overexpression of histone H2A modulates drug susceptibility in Leishmania parasites

Singh, Ruchi; Kumar, Deepak; Duncan, Robert C.; Nakhasi, Hira L.; Salotra, Poonam

doi:10.1016/j.ijantimicag.2010.03.012

Cited by 49 publications

(49 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The overexpression of MRPA observed in 2 resistant isolates in the current study was also described previously (11,45). GSH1, which is generally overexpressed in either in vitro-selected mutants or clinical isolates, was overexpressed in 3 resistant isolates (10,11,45). Our survey is also in accordance with an earlier study that demonstrated MAPK and H4 overexpression (45).…”

Section: Discussionsupporting

confidence: 92%

“…MRPA was the first molecular target that displayed gene amplification in Leishmania in vitro mutants selected with heavy metals, and this amplification was subsequently demonstrated in resistant field isolates (8)(9)(10). The overexpression of MRPA observed in 2 resistant isolates in the current study was also described previously (11,45). GSH1, which is generally overexpressed in either in vitro-selected mutants or clinical isolates, was overexpressed in 3 resistant isolates (10,11,45).…”

Section: Discussionsupporting

confidence: 76%

“…Apart from this high threshold, the absence of significant molecular resistance patterns in almost half of the resistant isolates could be associated with the involvement of other genes not investigated in our survey (10,11,15,20).…”

Section: Discussionmentioning

confidence: 84%

“…In fact, AQP1 is a membranous channel through which the trivalent antimony enters the parasite, and AQP1 overexpression is typically observed in susceptible isolates (11,45,47). However, a few cases of AQP1 overexpression in L. donovaniresistant clinical isolates have been reported (18,19).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, resistant Leishmania strains that are selected in vitro against several drugs, such as methotrexate, arsenicals, and antimonials, display amplification of extrachromosomal DNA forms termed H circles, which harbor the ABC transporter P-glycoprotein A (PGPA) (7,8,9). DNA amplification, gene overexpression, and elevated protein levels have also been displayed for other genes implicated in several metabolic pathways, including primarily drug entry, thiol metabolism, peroxide detoxification, and programmed cell death (10)(11)(12)(13)(14)(15)(16). Most of these studies were performed with in vitro-selected mutants of various Leishmania strains, mainly of the nonpatho-genic species Leishmania tarentolae (9,14,16,17).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Heterogeneity of Molecular Resistance Patterns in Antimony-Resistant Field Isolates of Leishmania Species from the Western Mediterranean Area

Jeddi

Mary

Karim

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

h Antimonials remain the first-line treatment for the various manifestations of leishmaniasis in most areas where the disease is endemic, and increasing cases of therapeutic failure associated with parasite resistance have been reported. In this study, we assessed the molecular status of 47 clinical isolates of Leishmania causing visceral and cutaneous leishmaniasis from Algeria, Tunisia, and southern France. In total, we examined 14 genes that have been shown to exhibit significant variations in DNA amplification, mRNA levels, or protein expression with respect to resistance to antimonials. The gene status of each clinical isolate was assessed via qPCR and qRT-PCR. We then compared the molecular pattern against the phenotype determined via an in vitro sensitivity test of the clinical isolates against meglumine antimoniate, which is considered the reference technique. Our results demonstrate significant DNA amplification and/or RNA overexpression in 56% of the clinical isolates with the resistant phenotype. All clinical isolates that exhibited significant overexpression of at least 2 genes displayed a resistant phenotype. Among the 14 genes investigated, 10 genes displayed either significant amplification or overexpression in at least 1 clinical isolate; these genes are involved in several metabolic pathways. Moreover, various gene associations were observed depending on the clinical isolates, supporting the multifactorial nature of Leishmania resistance. Molecular resistance features were found in the 3 Leishmania species investigated (Leishmania infantum, Leishmania major, and Leishmania killicki). To our knowledge, this is the first report of the involvement of molecular resistance genes in field isolates of Leishmania major and Leishmania killicki with the resistance phenotype.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Heterogeneity of Molecular Resistance Patterns in Antimony-Resistant Field Isolates of Leishmania Species from the Western Mediterranean Area

Jeddi

Mary

Karim

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

Global distribution of treatment resistance gene markers for leishmaniasis

Salari

Bamorovat

Sharifi

et al. 2022

Clinical Laboratory Analysis

View full text Add to dashboard Cite

The protozoan parasites belonging to the genus Leishmania are pathogenic agents of a complex and non-contagious disease, leishmaniasis. 1,2 Different clinical manifestations are present for this tropical disease ranging from benign self-healing cutaneous (CL) and mucocutaneous (MCL) to a deadly visceral (VL) leishmaniasis. 3 The major species to cause CL in the Old World consist of Leishmania major (L. major) and Leishmania tropica (L. tropica). 4 Over 70% of the global CL cases occur in Algeria,

show abstract

Drug Resistance in Leishmania

Légaré

Ouellette

2014

Handbook of Antimicrobial Resistance

View full text Add to dashboard Cite

Protozoan parasites of the genus Leishmania cause a wide range of diseases affecting 12 million people worldwide with 1.5-2 million new cases each year. With no vaccine available yet, the control of these parasites relies solely on chemotherapy. Low-cost antimony-derived compounds remain the primary antileishmanial treatment in most developing countries. Increasing drug resistance towards these molecules has forced the use of alternative therapies in highly endemic areas including amphotericin B, paromomycin, and miltefosine. This chapter is presenting our current understanding of the mode of action and underlying resistance mechanisms of the few therapeutic drugs used against Leishmania. Keywords

show abstract

Overexpression of histone H2A modulates drug susceptibility in Leishmania parasites

Cited by 49 publications

References 37 publications

Heterogeneity of Molecular Resistance Patterns in Antimony-Resistant Field Isolates of Leishmania Species from the Western Mediterranean Area

Heterogeneity of Molecular Resistance Patterns in Antimony-Resistant Field Isolates of Leishmania Species from the Western Mediterranean Area

Global distribution of treatment resistance gene markers for leishmaniasis

Drug Resistance in Leishmania

Contact Info

Product

Resources

About