Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan

Marquet, Sandrine; Bucheton, Bruno; Reymond, Camille; Argiro, Laurent; El-Safi, Sayda; Kheir, Musa M.; Desvignes, Jean-Pierre; Béroud, Christophe; Mergani, Adil; Hammad, Awad; Dessein, Alain

doi:10.1093/infdis/jix277

Cited by 12 publications

(7 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sudan and South Sudan are dominated by VL and CL, with a man being a reservoir host [36] quite unique from the Indian type where canine act as reservoirs [7,37]. African Kala-azar, engulf South Sudan and Sudan with rare epidemiological characteristics of disease manifestation from other global types of Kala-azar [38], the distinctive feature is a primary initiation phase in the skin (Leishmanoma) [39] takes time before the onset of clinical symptoms [37]. Utmost importance for epidemiological identification of Sudanese kala-azar [38,39].…”

Section: Ld Epidemiology and Disease Occurrence In South Sudan And Smentioning

confidence: 99%

Visceral Leishmaniasis: Evaluation of Diagnostic Tools, Therapeutic Regimens, and Associated Risk Factors in Areas with Frequent Outbreaks in South Sudan and Sudan: Case Reports and Review of Literature

Amanya¹,

Peng²

2018

J Trop Dis

View full text Add to dashboard Cite

Introduction: Visceral leishmaniasis of genus Leishmania donovani is a known cause of Kala-azar, with an agent of Phlebotomus species. Other species of public health importance include Phlebotomus-martini that engulfed South Sudan bordering counties with Kenya whereas Phlebotomus-orientalis dominates northern parts of South Sudan and Sudan. It exhibits rare behavioral characteristics of outer door bites. Among Eastern African countries, South Sudan is a highly endemic area where more than 1/3 of the population is at risks of infections. This review aimed to evaluate the current diagnosis, treatment and risk factors associated with epidemics and mortality due to Visceral Leishmaniasis in Sudan and South Sudan. Methodology and Objective:Literatures published in SCI Journals, pub med, and science direct, Google, WHO reports, MSF, and CDC websites were searched starting from 1945 to 2018. Visceral leishmaniasis/VL diagnostic tools, treatment regimens, and associated risk factors were the keywords used during browsing. Details referred to Given Figures in the methodology section.Findings: Several risk factors contributed to the frequency of VL outbreaks. Chronic wars, malnutrition and settlement in areas infested by the sand fly, co-infections with either HIV or Hepatitis an emerging public health concern. Government efforts to control and eliminates the vectors of VL are lacking with negligible resources allocation. Acacia trees are proved to harbor sand fly as resting and hiding places. K39/K26 or rk39/rk28 dipstick is a field base diagnostic tool commonly used. Treatments with liposomal AmporicinB, sodium stibogluconate plus paromomycin are recommended for use in South Sudan. This review also revealed that areas formerly free from Kala-azar had experience recurrent epidemic.Conclusion: VL in South Sudan remains highly isolated from clinical diagnosis, treatment, and control strategies. Routine data for surveillance is also an absence. National guidelines and protocols for treatment, and vector control remain at standstill. The level of resistance of visceral Leishmania parasites to the available anti-leishmanial drugs required more researches. There is a close relationship between frequent VL outbreaks and internal conflicts, poor malnutrition, poverty and displacement to high transmission zones, individuals who are new in sand fly infested areas are at greater risks, including children, elderly and pregnant women.

show abstract

Section: Ld Epidemiology and Disease Occurrence In South Sudan And Smentioning

confidence: 99%

Visceral Leishmaniasis: Evaluation of Diagnostic Tools, Therapeutic Regimens, and Associated Risk Factors in Areas with Frequent Outbreaks in South Sudan and Sudan: Case Reports and Review of Literature

Amanya¹,

Peng²

2018

J Trop Dis

View full text Add to dashboard Cite

show abstract

“…Such a role was described by Marquet et al [ 1 ], through their identification of 2 AGMO variants: (1) a missense variant in exon 7 (c.701A>G, rs143439626, p.Lys234Arg, K234R) and (2) a nonsense variant in exon 12 (c.1213C>T, rs139309795, p.Arg405*, R405X). In all families in this study, the 2 alleles cosegregate (data for individual 5 in family 1 are most likely a genotyping error) and, thus, are positioned on the same allele in a cis configuration.…”

mentioning

confidence: 94%

“…To the Editor —Marquet et al [ 1 ] recently described 2 variants in AGMO associated with relapses in visceral leishmaniasis ( kala-azar [KA]) in Sudanese children. This gene codes for the ether lipid–cleaving enzyme alkylglycerol monooxygenase (AGMO), a membrane-bound enzyme expressed in a variety of tissues and cell lines [ 2 ] but also in primary murine macrophages, where it is differentially regulated in inflammatory and antiinflammatory priming of the cells [ 3 ].…”

mentioning

confidence: 99%

“…For the double-mutant p.[Lys234Arg;Arg405*], protein expression decreased to a level similar to that for p.Arg405* alone (to 39.3% of the wild type value), but cellular activity tended to be further suppressed (to 5.33%), although this was not significantly different from observations for p.Arg405* alone ( P = .78). Based on the data from Marquet et al [ 1 ], cosegregation of the p.Lys234Arg variant with the p.Arg405* variant explains why p.Lys234Arg, which, on its own, is functionally silent, was interpreted to be associated with the disease.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Biochemical Characterization of AGMO Variants Implicated in Relapses in Visceral Leishmaniasis

Watschinger

Keller

Golderer

et al. 2018

The Journal of Infectious Diseases

View full text Add to dashboard Cite

“…There are few VL relapses reports and those which have it, present a great variability in the incidence of relapses according to the population and regions studied [27][28][29][30]. In a Spanish cohort, VL relapse rate was 12% [27] while in Sudan, the clinical follow-up during an epidemic in Babar showed 5.7% of relapses, most of patients concentrated in few families [31]. A previous Brazilian study showed relapse in 2.3% of children diagnosed with VL between 2006 and 2011 [30].…”

mentioning

confidence: 99%

High Levels of anti-Leishmania IgG3 and Low CD4+ T Cells Count were Associated with Relapses in Visceral Leishmaniasis

Kuschnir

Pereira

Dutra

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Visceral leishmaniasis (VL) is severe and potentially fatal. Brazil is one of the countries with the greatest endemicity for the disease in the world. The reduction of CD4+ T lymphocytes, B cells activation and high levels of inflammatory cytokines (IL-6/IL-8/TNF/IL-1β), plasma LPS, soluble CD14, anti-Leishmania IgG3 and low leptin levels are involved in the immunopathogenesis of VL, most associated with severe VL. Despite relapses occurring in about 4-5% of patients with VL not associated with HIV infection, the factors underlying relapses are little known. Our aim was to identify clinical, laboratory and immunological parameters that may be associated with recurrences in VL.Methods: Fifteen VL patients recruited from Hospital Eduardo de Menezes (BH-MG) were grouped into relapsing (R-VL, n=5) and non-relapsing (NR-VL, n=10) and evaluated during active disease, immediately after treatment (post-treatment) and six months post-treatment (6mpt). Clinical and laboratory data obtained from medical records were correlated with CD4+ and CD8+ T cell counts and anti-Leishmania Igs and IL-6 plasma levels and compared to those parameters of ten healthy controls.Results: During the active phase of VL, despite similarity in the clinical symptoms, the rates of thrombocytopenia, elevated transaminases (AST and ALT) and hyperbilirubinemia were higher in the NR-VL group compared to R-VL (p<0.05), a profile reversed during the post-treatment phase. All patients had low CD4+ T counts in active phase, however, NR-VL patients had a higher gain of this cell type than R-VL in the post-treatment (p<0.05). There was a significant reduction in IgG3 levels during the follow-up in the NR-VL group compared to the R-VL, especially at 6mpt (p<0.05). In addition, IgG3 levels were negatively correlated with CD4+ T counts in the R-VL group (r=-0.52). Elevated levels of IL-6 were observed in active VL and correlated with clinical markers of severity. Conclusions: During active phase of VL, the NR-VL patients presented more severe laboratorial abnormalities compared to R-VL, probably because the latter had already received previous treatment. On the other hand, R-VL exhibited greater impairment of immune reconstitution and a high degree of B lymphocyte activation, which must be a factor that favored relapses.

show abstract

Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan

Abstract: This is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity.

Cited by 12 publications

References 45 publications

Visceral Leishmaniasis: Evaluation of Diagnostic Tools, Therapeutic Regimens, and Associated Risk Factors in Areas with Frequent Outbreaks in South Sudan and Sudan: Case Reports and Review of Literature

Visceral Leishmaniasis: Evaluation of Diagnostic Tools, Therapeutic Regimens, and Associated Risk Factors in Areas with Frequent Outbreaks in South Sudan and Sudan: Case Reports and Review of Literature

Biochemical Characterization of AGMO Variants Implicated in Relapses in Visceral Leishmaniasis

High Levels of anti-Leishmania IgG3 and Low CD4+ T Cells Count were Associated with Relapses in Visceral Leishmaniasis

Contact Info

Product

Resources

About