Biology subjects

Hailu, A.

Publications and source records attributed to Hailu, A..

3 recordsLinked to original sources

bioRxiv2026

Decoding Ethiopia's unique and structurally divergent Plasmodium falciparum populations using genomics

Previous genome-wide studies suggest that Ethiopian Plasmodium falciparum parasites are unique and structurally divergent from sub-Saharan African populations but were limited by small sample sizes. The emergence of molecular markers associated with reduced artemisinin susceptibility in northern Ethiopia, and the drug pressures created by sympatric P. falciparum and P. vivax, may have fostered a distinct and permissive genetic background for the emergence and spread of multidrug resistant parasites. To characterise parasite population structure and evolutionary dynamics in this setting, we generated whole-genome sequencing data for 163 P. falciparum isolates from southern Ethiopia (2017-2021) and integrated these with 854 isolates from across sub-Saharan Africa. Ethiopian parasites exhibited markedly reduced diversity, highly conserved genomes, and distinct admixture ancestry. Near-fixation of chloroquine and antifolate associated resistance markers, potentially driven by P. vivax co-circulation, suggests persistent drug-related selection pressures. We identified a previously undescribed deletion in the pfmdr1 5' UTR that is common in Ethiopia and potentially widespread across African populations. Although clinically relevant pfk13 variants have emerged in northern Ethiopia, these were not detected in southern Ethiopia. However, strong genetic connectivity between regions indicates the potential for rapid spread of resistance and is therefore important for public health policy and practice.

genomics↗

bioRxiv2019

Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given low attention in drug discovery researches to narrow the existing gap in safety and efficacy of the currently used drugs to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Aiming to look for potential anti-leishmanial hits and leads, we screened MMV Pathogen Box against clinically isolated L. donovani strain. Compounds were screened against promastigote, and then against amastigote stages; of which, 35 compounds showed >50% inhibition on promastigotes in the initial screen (1 M). Out of these compounds, 9 compounds showed >70% inhibition with median inhibitory concentration (IC50) ranges from 12 nM to 491 nM on anti-promastigote assay and 53 to 704 nM on intracellular amastigote assay. Identified compounds demonstrated good safety on THP-1 cell lines and sheep RBCs, and appropriate physico-chemical property suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as lead compounds. Among these compounds, anti-tubercular agent MMV688262 (delamanid) showed synergistic effect with amphotericin B, indicating the prospect of this compound for combination therapy. The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure activity relationship studies. Future works also needs to investigate antiamastigotes activity of remaining hits, which were not covered in the present study.\n\nAuthors summaryVisceral leishmaniasis is a major public health problem in endemic regions. Different drugs have been used to treat visceral leishmaniasis. However, the available drugs are either toxic, non-compliance to the patient, painful upon administration, low in efficacy, or costly. New chemical entities that overcome the limitations of existing drugs are therefore desperately needed. Screening of 400 pathogen box compounds against of Leishmania donovani clinical isolate resulted in identification of 35 compounds with >50% inhibition against promastigotes at 1 M. Out of these compounds, 9 showed >70% inhibition with median inhibitory concentration ranges from 12 nM to 491 nM on anti-promastigote assay, and 53 to 704 nM on intracellular amastigote assay. Our work identified new compounds which hold promise for further drug development.

pharmacology and toxicology↗

bioRxiv2019

Genomic analysis of natural intra-specific hybrids among Ethiopian isolates of Leishmania donovani

Parasites of the genus Leishmania (Kinetoplastida: Trypanosomatidae) cause widespread and devastating human diseases, ranging from self-healing but disfiguring cutaneous lesions to destructive mucocutaneous presentations or usually fatal visceral disease. Visceral leishmaniasis due to Leishmania donovani is endemic in Ethiopia where it has also been responsible for major epidemics. The presence of hybrid genotypes has been widely reported in surveys of natural populations, genetic variation reported in a number of Leishmania species, and the extant capacity for genetic exchange demonstrated in laboratory experiments. However, patterns of recombination and evolutionary history of admixture that produced these hybrid populations remain unclear, as most of the relevant literature examines only a limited number (typically fewer than 10) genetic loci. Here, we use whole-genome sequence data to investigate Ethiopian L. donovani isolates previously characterised as hybrids by microsatellite and multi-locus sequencing. To date there is only one previous study on a natural population of Leishmania hybrids, based on whole-genome sequence. The current findings demonstrate important differences. We propose hybrids originate from recombination between two different lineages of Ethiopian L. donovani occurring in the same region. Patterns of inheritance are more complex than previously reported with multiple, apparently independent, origins from similar parents that include backcrossing with parental types. Analysis indicates that hybrids are representative of at least three different histories. Furthermore, isolates were highly polysomic at the level of chromosomes with startling differences between parasites recovered from a recrudescent infection from a previously treated individual. The results demonstrate that recombination is a significant feature of natural populations and contributes to the growing body of evidence describing how recombination, and gene flow, shape natural populations of Leishmania.\n\nAuthor SummaryLeishmaniasis is a spectrum of diseases caused by the protozoan parasite Leishmania. It is transmitted by sandfly insect vectors and is responsible for an enormous burden of human suffering. In this manuscript we examine Leishmania isolates from Ethiopia that cause the most serious form of the disease, namely visceral leishmaniasis, which is usually fatal without treatment. Historically the general view was that such parasites reproduce clonally, so that their progeny are genetically identical to the founding cells. This view has changed over time and it is increasingly clear that recombination between genetically different Leishmania parasites occurs. The implication is that new biological traits such as virulence, resistance to drug treatments or the ability to infect new species of sandfly could emerge. The frequency and underlying mechanism of such recombination in natural isolates is poorly understood. Here we perform a detailed whole genome analysis on a cohort of hybrid isolates from Ethiopia together with their potential parents to assess the genetic nature of hybrids in more detail. Results reveal a complex pattern of mating and inbreeding indicative of multiple mating events that has likely shaped the epidemiology of the disease agent. We also show that some hybrids have very different relative amounts of DNA (polysomy) the implications of which are discussed. Together the results contribute to a fuller understanding of the nature of genetic recombination in natural populations of Leishmania.

genomics↗