Biology subjects

Mfarrej, S.

Publications and source records attributed to Mfarrej, S..

6 recordsLinked to original sources

bioRxiv2026

Malaria parasites coordinate host cell remodeling through the AP2-HCR DNA-binding protein

Parasite-induced host cell remodeling is essential for Plasmodium falciparum survival during the intraerythrocytic developmental cycle (IDC), yet the transcriptional mechanisms coordinating this process remain poorly understood. Here, we characterize an essential ApiAP2 transcription factor, PfAP2-HCR (host cell remodeling), during both the asexual and sexual blood stages of P. falciparum. Conditional truncation of pfap2-hcr demonstrated that PfAP2-HCR is essential for ring stage development and parasite maturation. Loss of PfAP2-HCR disrupted the expression of host cell remodeling genes, resulting in the absence of Maurers clefts and collapse of the parasite protein export machinery. Integrated RNA-seq and ChIP-seq analyses revealed that PfAP2-HCR directly or indirectly regulates approximately 30% of exported proteins, including 27 essential exported factors, the parasitophorous vacuole membrane (PVM) resident protein EXP1, and the core PTEX component EXP2. We further show that PfAP2-HCR is also indispensable for gametocytogenesis, as conditional truncation results in either complete ablation or the formation of severely deformed gametocytes. Together, these findings establish PfAP2-HCR as a central transcriptional regulator that orchestrates the expression of host cell remodeling factors required to transform a terminally differentiated erythrocyte into a permissive environment for parasite survival, development, and transmission.

microbiology↗

bioRxiv2023

PfAP2-MRP DNA-binding protein is a master regulator of parasite pathogenesis during malaria parasite blood stages

Malaria pathogenicity results from the parasites ability to invade, multiply within and then egress from the host red blood cell (RBC). Infected RBCs are remodeled, expressing antigenic variant proteins (such as PfEMP1, coded by the var gene family) for immune evasion and survival. These processes require the concerted actions of many proteins, but the molecular regulation is poorly understood. We have characterized an essential Plasmodium specific Apicomplexan AP2 (ApiAP2) transcription factor in Plasmodium falciparum (PfAP2-MRP; Master Regulator of Pathogenesis) during the intraerythrocytic developmental cycle (IDC). An inducible gene knockout approach showed that PfAP2-MRP is essential for development during the trophozoite stage, and critical for var gene regulation, merozoite development and parasite egress. ChIP-seq experiments performed at 16 hour post invasion (h.p.i.) and 40 h.p.i. matching the two peaks of PfAP2-MRP expression, demonstrate binding of PfAP2-MRP to the promoters of genes controlling trophozoite development and host cell remodeling at 16 h.p.i. and antigenic variation and pathogenicity at 40 h.p.i. Using single-cell RNA-seq and fluorescence-activated cell sorting, we show de-repression of most var genes in{Delta} pfap2-mrp parasites that express multiple PfEMP1 proteins on the surface of infected RBCs. In addition, the{Delta} pfap2-mrp parasites overexpress several early gametocyte marker genes at both 16 and 40 h.p.i., indicating a regulatory role in the sexual stage conversion. Using the Chromosomes Conformation Capture experiment (Hi-C), we demonstrate that deletion of PfAP2-MRP results in significant reduction of both intra-chromosomal and inter-chromosomal interactions in heterochromatin clusters. We conclude that PfAP2-MRP is a vital upstream transcriptional regulator controlling essential processes in two distinct developmental stages during the IDC that include parasite growth, chromatin structure and var gene expression.

genomics↗

bioRxiv2023

Reverse chemical ecology approach for sustainable palm tree protection against invasive palm weevils

The reverse chemical ecology approach facilitates sustainable plant protection by identifying odorant receptors (ORs) tuned to odorants, especially the volatile molecules emitted from host plants that insects use for detection. A few studies have explored such an approach to develop sustainable pest management programs, especially in host-specialized insect species. We revealed the molecular mechanism of host plant detection of a destructive, invasive insect pest of palm trees (Arecaceae), the Asian palm weevil (Rhynchophorus ferrugineus), by deorphanizing an OR (RferOR2) tuned to several palm-emitted odors. We found that RferOR2 responded explicitly to several ecologically relevant palm-emitted odors and significantly to palm esters when transgenically expressed in Drosophila olfactory neurons. We mapped RferOR2 expression in the R. ferrugineus genome and found that odor specificity is likely to develop equally in both sexes. We inferred that the semiochemicals that attract palm weevils to a palm tree might aid in weevil control efforts by improving attraction, enticing many palm weevils to the traps. We demonstrate that including synthetic palm volatiles in pheromone-based mass trapping has a synergistic effect on pheromones, resulting in significantly increased weevil catches. We proved that insect OR deorphanization could aid in the identification of novel behaviorally active volatiles for inclusion in pest management. These results suggest that targeting RferOR2 may help design receptor antagonists that can interfere with weevil host-searching behavior in sustainable pest management applications. SignificanceAsian and South American palm weevils are tremendously important agricultural pests primarily adapted to palm trees and cause severe destruction, threatening sustainable palm cultivation worldwide. The host plant selection of these weevils is mainly attributed to functional specialization of odorant receptors that detect palm-derived volatiles. We unraveled the intricacies of weevil-palm tree communication by deorphanizing an odorant receptor tuned to natural palm-emitted odors. We used palm ester volatiles, which produced a significant response in the functional studies, and proved their synergistic effect on the pheromone coinciding with increased weevil catches in the field. We revealed that insect odorant receptor deorphanization could help identify novel behaviorally active volatiles (reverse chemical ecology) for sustainable palm protection.

ecology↗

bioRxiv2022

Theileria annulata histone deacetylase 1 (TaHDAC1) initiates schizont to merozoite stage conversion

A fungal metabolite, FR235222, specifically inhibits a histone deacetylase of the apicomplexan parasite Toxoplasma gondii and TgHDAC3 has emerged as a key factor regulating developmental stage transition in this species. Here, we exploited FR235222 to ask if changes in histone acetylation regulate developmental stage transition of Theileria annulata, another apicomplexan species. We found that FR235222 treatment of T. annulata-infected transformed leukocytes induced a proliferation arrest. The blockade in proliferation was due to drug-induced conversion of intracellular schizonts to merozoites that lack the ability to maintain host leukocyte cell division. Induction of merogony by FR235222 leads to an increase in expression of merozoite-marker (rhoptry) proteins. RNA-seq of FR235222-treated T. annulata-infected B cells identified deregulated expression of 468 parasite genes including a number encoding parasite ApiAP2 transcription factors. Thus, similar to T. gondii, FR235222 inhibits T. annulata HDAC (TaHDAC1) activity and places parasite histone acetylation as a major regulatory event of the transition from schizonts to merozoites.

cell biology↗

bioRxiv2020

The pangenome analysis of the soil-borne fungal phytopathogen Rhizoctonia solaniand development of a comprehensive web resource: RsolaniDB

Rhizoctonia solani is a collective group of genetically and pathologically diverse basidiomycetous fungus that damages economically important crops. Its isolates are classified into 13 Anastomosis Groups (AGs) and subgroups having distinctive morphology and host range. The genetic factors driving the unique features of R. solani pathology are not well characterized due to the limited availability of its annotated genomes. Therefore, we performed genome sequencing, assembly, annotation and functional analysis of 12 R. solani isolates covering 7 AGs and selected subgroups (AG1-IA, AG1-IB, AG1-IC, AG2-2IIIB, AG3-PT (isolates Rhs 1AP and the hypovirulent Rhs1A1), AG3-TB, AG4-HG-I (isolates Rs23 and R118-11), AG5, AG6, and AG8), in which six genomes are reported for the first time, wherein we discovered unique and shared secretomes, CAZymes, and effectors across the AGs. Using a pangenome comparative analysis of 12 R. solani isolates and 15 other basidiomycetes, we also elucidated the molecular factors potentially involved in determining the AG-specific host preference, and the attributes distinguishing them from other Basidiomycetes. Finally, we present the largest repertoire of R. solani genomes and their annotated components as a comprehensive database, viz. RsolaniDB, with tools for large-scale data mining, functional enrichment and sequence analysis not available with other state-of-the-art platforms, to assist mycologists in formulating new hypotheses.

genomics↗

bioRxiv2019

Mycobacterium riyadhense clinical isolates provide insights into ancestry and adaptive evolution in tuberculosis

Current evolutionary scenarios posit the emergence of Mycobacterium tuberculosis, the deadliest bacterial pathogen for humans globally, from an environmental saprophyte through a cumulative process of genome adaptation. Mycobacterium riyadhense is a novel non-tuberculous mycobacterium (NTM) that is being increasingly isolated from human clinical cases with tuberculosis (TB)-like symptoms in various parts of the world. We provide evidence here that M. riyadhense is likely a missing link in our understanding of the evolution of M. tuberculosis. To elucidate the genomic hallmarks that define the evolutionary relationship between M. riyadhense and other mycobacterial species, including members of the Mycobacterium tuberculosis complex (MTBC), eight clinical isolates of M. riyadhense were sequenced and analyzed. We show, among other features, that M. riyadhense shares a large number of conserved orthologues with the MTBC; contains linear and circular plasmids carrying type IV and type VII secretion systems; and shows expansion of toxin/anti-toxin pairs. We conclude that M. riyadhense is an emerging mycobacterial pathogen that shares a common ancestor with members of the MTBC and that can serve as an experimental model to study the evolution and pathogenesis of tubercle bacilli.\n\nAuthor summaryMycobacterium tuberculosis is one of the most prolific infectious killers in humans and is a member of the Mycobacterium tuberculosis complex (MTBC) - a group of genetically related pathogens that cause tuberculosis (TB) in mammalian species. It is postulated that MTBC has evolved from a free-living environmental ancestor into an obligate pathogen. In this evolutionary context, a comprehensive understanding of the genomic hallmarks of the free-living environmental ancestors of the MTBC is of particular scientific interest for better understanding of the evolution of the MTBC. Mycobacterium riyadhense is a novel environmental mycobacterium, first isolated in 2009 in a hospital in Riyadh, that is increasingly being isolated from clinical cases with typical tuberculosis (TB)-like symptoms in humans. In this study, we report the characterization of eight clinical isolates of M. riyadhense, compare their genomes to members of the MTBC, and provide a comprehensive insight into the adaptive changes associated with the evolution of the MTBC from environmental mycobacteria. We show that M. riyadhense is one of the closest known environmental mycobacteria related to the MTBC, and we provide several lines of molecular evidence that M. riyadhense is likely the missing link in the evolution of M. tuberculosis. It shares a common ancestor with members of the MTBC that have evolved through a process of genome reduction, expansion of toxin/antitoxin (T/A) gene systems, and ultimately host adaptation.

evolutionary biology↗