Biology subjects

Noorai, R. E.

Publications and source records attributed to Noorai, R. E..

9 recordsLinked to original sources

bioRxiv2026

Intrinsic protein disorder reveals divergent signaling architectures and lifestyle adaptation in Entamoeba species

Intrinsic protein disorder plays a central role in cellular regulation and host-pathogen interactions, yet its proteome-wide distribution and functional organization in amoebozoan parasites remain poorly understood. Here, we present the first comparative analysis of intrinsic disorder across the proteomes of Entamoeba histolytica, which causes amoebic dysentery, and two related species, E. dispar, and E. invadens. For comparison, we analyzed intrinsic protein disorder in two phylogenetically distant parasites, Plasmodium falciparum and Trypanosoma brucei. Overall, Entamoeba species exhibited significantly lower levels of intrinsic disorder than P. falciparum and T. brucei. Despite this, all organisms displayed a conserved functional trend in which increasing disorder was associated with a shift from metabolic and catalytic processes toward gene expression-related functions. However, notable organism-specific differences emerged. P. falciparum showed persistent enrichment of gene expression functions across all disorder levels, while T. brucei maintained metabolic, redox, and transport processes throughout the disorder spectrum. In contrast, Entamoeba species uniquely retained GTPase- and phosphorylation-associated signaling across all levels of disorder, with the strongest enrichment observed in the pathogenic species, E. histolytica and E. invadens. This pattern likely reflects a reliance on rapid environmental sensing, cytoskeletal remodeling, and vesicle trafficking, necessary for successful infection. Consistent with this, there was reduced enrichment of G-protein signaling in the non-pathogenic commensal, E. dispar, especially in highly disordered proteins. Secretome analysis further revealed that, unlike P. falciparum, E. histolytica possesses a more structurally ordered secretome, suggesting selection for stable catalytic proteins in the host intestinal environment. Finally, no consistent relationship was identified between intrinsic disorder and vaccine efficacy for several key antigenic targets. Together, these findings demonstrate that intrinsic disorder is differentially deployed across parasites, and utilization of disordered proteins has diverged in accordance with each organisms lifecycle and host interaction strategy. These findings highlight the role of intrinsic disorder in shaping parasitism.

microbiology↗

bioRxiv2025

Genetic determinants that permit growth without the core septin Cdc12 in Cryptococcus neoformans

Septins are conserved cytoskeletal GTPases that regulate morphogenesis, cytokinesis, and cell-surface organization in fungi. In most model and pathogenic yeasts, including Saccharomyces cerevisiae and Candida albicans, core septin subunits such as Cdc3 and Cdc12 are essential and their loss results in lethal cytokinetic defects. In Cryptococcus neoformans, by contrast, deletion of CDC12 yields viable cells that grow normally under permissive conditions, raising the question of how this pathogen maintains cell integrity without a functional septin complex. To address this, we compared the transcriptomes of wild-type cells and a cdc12{Delta} mutant. The cdc12{Delta} strain showed a focused set of transcriptional changes, with induction of genes involved in cell wall remodeling, stress-dependent morphogenetic programs, and pathways that promote fitness under compromised cytoskeletal conditions. Genetic analysis of the most highly induced genes uncovered factors that contribute to proliferation in the absence of Cdc12, including a previously uncharacterized aspartic-type endopeptidase that becomes essential when septin function is lost. These findings outline the compensatory circuitry that permits septin-independent growth in C. neoformans and help explain why this pathogen can tolerate septin loss. This intrinsic plasticity highlights C. neoformans as a powerful comparative model for studying the evolution and function of the septin complex.

microbiology↗

bioRxiv2025

A long non-coding RNA regulates triazole antifungal susceptibility and virulence in Aspergillus fumigatus

Azole-resistant Aspergillus infections are a source of increasing concern with limited alternative therapeutic options. However, as most infections are still caused by azole-susceptible Aspergillus strains, there is a need to better understand fungal responses to azole antifungals. To this end, we discover that a long non-coding RNA, afu-182, is a major regulator of cyp51-independent sub-MIC azole response. We observe that loss of afu-182 leads to increased surface attached growth and poor treated disease outcomes in a murine model of invasive pulmonary aspergillosis upon azole treatment. In contrast, overexpression of afu-182 significantly reduces fungal burden in animals treated with the azole drug, posaconazole. Importantly, afu-182 levels decrease upon azole exposure and in an azole adaptation experiment, continuous exposure to low dose azole led to MIC increase in an afu-182 dependent manner. Whole transcriptome analyses revealed that azole drug treatment leads to an increase in transcripts of genes encoding 7-transmembrane domain proteins of the RTA1 family, and these proteins are negatively regulated by afu-182. Two RTA1 family genes have individual and combined effects and are sufficient to increase fungal susceptibility to azole drugs in the WT strain. Taken together, our data show a role of the long non-coding RNA afu-182 in regulating Aspergillus fumigatus response to azole drugs both in vitro and in vivo. ImportanceDrug resistance in Aspergillus is a major challenge that is often associated with the agricultural use of azoles in the environment. How drug resistance arises in vivo is still an active area of research. Here, we show that azole exposure results in fungal adaptation by lowering the RNA levels of lncRNA, which upon low dose azole exposure leads to an increase in azole drug MIC.

molecular biology↗

bioRxiv2024

Climate Adaptation and Genetic Differentiation in the Mosquito Species Culex tarsalis

The increasing prevalence of vector-borne diseases around the world highlights the pressing need for an in-depth exploration of the genetic and environmental factors that shape the adaptability and widespread distribution of mosquito populations. This research focuses on Culex tarsalis, a principal vector for various viral diseases including West Nile Virus (WNV). Through the development of a new reference genome and the examination of Restriction-Site Associated DNA sequencing (RAD-seq) data from over 300 individuals and 28 locations, we demonstrate that variables such as temperature, evaporation rates, and the density of vegetation significantly impact the genetic makeup of Cx. tarsalis populations. Among the alleles most strongly associated with environmental factors is a nonsynonymous mutation in a key gene related to circadian rhythms. These results offer new insights into the mechanisms of spread and adaptation in a key North American vector species, which is poised to become a growing health threat to both humans and animals in the face of ongoing climate change.

genomics↗

bioRxiv2023

TML1 AND TML2 SYNERGISTICALLY REGULATE NODULATION BUT NOT ARBUSCULAR MYCORRHIZA IN MEDICAGO TRUNCATULA

Two symbiotic processes, nodulation and arbuscular mycorrhiza, are primarily controlled by the plants need for nitrogen (N) and phosphorus (P), respectively. Autoregulation of Nodulation (AON) and Autoregulation of Mycorrhization (AOM) both negatively regulate their respective processes and share multiple components - plants that make too many nodules usually have higher AM fungal root colonization. The protein TML (TOO MUCH LOVE) was shown to function in roots to maintain susceptibly to rhizobial infection under low N conditions and control nodule number through AON in Lotus japonicus. M. truncatula has two sequence homologs: MtTML1 and MtTML2. We report the generation of stable single and double mutants harboring multiple allelic variations in MtTML1 and MtTML2 using CRISPR-Cas9 targeted mutagenesis and screening of a transposon mutagenesis library. Plants containing single mutations in MtTML1 or MtTML2 produced 2-3 times the nodules of wild-type plants whereas plants containing mutations in both genes displayed a synergistic effect, forming 20x more nodules compared to wild type plants. Examination of expression and heterozygote effects suggest genetic compensation may play a role in the observed synergy. Plants with mutations in both TMLs only showed mild increases in AM fungal root colonization at later timepoints in our experiments, suggesting these genes may also play a minor role in AM symbiosis regulation. The mutants created will be useful tools to dissect the mechanism of synergistic action of MtTML1 and MtTML2 in M. truncatula symbiosis with beneficial microbes.

molecular biology↗

bioRxiv2020

The transcriptome of Balamuthia mandrillaris trophozoites for structure-based drug design

Balamuthia mandrillaris, a pathogenic free-living amoeba (FLA), causes cutaneous skin lesions as well as the brain-eating disease: Balamuthia granulomatous amoebic encephalitis (GAE). These diseases, and diseases caused by other pathogenic FLA, Naegleria fowleri or Acanthamoeba species, are minimally studied from a drug discovery perspective; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Chemotherapies for CNS disease caused by B. mandrillaris require vast improvement. Current therapeutics are limited to a small number of drugs that were previously discovered in the last century through in vitro testing or identified after use in the small pool of surviving reports. Using our recently published methodology to identify potentially useful therapeutics, we screened a collection of 85 compounds that have previously been reported to have antiparasitic activity. We identified 59 compounds that impacted growth at concentrations below 220 M. Since there is no fully annotated genome or proteome, we used RNA-Seq to reconstruct the transcriptome of B. mandrillaris and locate the coding sequences of the specific genes potentially targeted by the compounds identified to inhibit trophozoite growth. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing.

genomics↗

bioRxiv2019

The Chinese chestnut genome: a reference for species restoration

Forest tree species are increasingly subject to severe mortalities from exotic pests, diseases, and invasive organisms, accelerated by climate change. Forest health issues are threatening multiple species and ecosystem sustainability globally. While sources of resistance may be available in related species, or among surviving trees, introgression of resistance genes into threatened tree species in reasonable time frames requires genome-wide breeding tools. Asian species of chestnut (Castanea spp.) are being employed as donors of disease resistance genes to restore native chestnut species in North America and Europe. To aid in the restoration of threatened chestnut species, we present the assembly of a reference genome with chromosome-scale sequences for Chinese chestnut (C. mollissima), the disease-resistance donor for American chestnut restoration. We also demonstrate the value of the genome as a platform for research and species restoration, including new insights into the evolution of blight resistance in Asian chestnut species, the locations in the genome of ecologically important signatures of selection differentiating American chestnut from Chinese chestnut, the identification of candidate genes for disease resistance, and preliminary comparisons of genome organization with related species.

genomics↗

bioRxiv2018

Glucose signaling is important for nutrient adaptation during differentiation of pleomorphic African trypanosomes

The African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its lifecycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites are rapidly killed as glucose concentrations fall, while the short stumpy bloodstream form parasites persist to differentiate into the insect stage procyclic form parasite. The rate of differentiation was slower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and its non-metabolizable analogs in a concentration dependent manner. Procyclic form parasites differentiated from short stumpy form parasites in glucose depleted medium significantly upregulated gene expression of amino acid metabolic pathway components when compared to procyclic forms generated by cis-aconitate treatment. Additionally, growth of these parasite was inhibited by the presence of either glucose or 6-deoxyglucose. In summary, glucose transitions from the primary metabolite of the blood stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but is also an important signaling molecule.\n\nAuthor SummaryAs the African trypanosome, Trypanosoma brucei, completes its lifecycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling lifecycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the non-dividing short stumpy remains viable and undergoes differentiation to the next lifecycle stage, the procyclic form parasite. Interestingly a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.

microbiology↗

bioRxiv2018

Identification of a post-transcriptional regulatory element that responds to glucose in the African trypanosome

The ability to adapt to varying nutrient availability in changing environments is critical for successful parasitism. The lifecycle stages of the African trypanosome, Trypanosoma brucei, that infect the host mammalian bloodstream utilize glucose exclusively for ATP production. The finding that trypanosomes also inhabit other tissues that frequently contain lower glucose concentrations suggests blood stage parasites may have to respond to a dynamic environment with changing nutrient availability in order to survive. However, little is known about how the parasites coordinate gene expression with nutrient availability. Through transcriptome analysis, we have found blood stage parasites deprived of glucose alter gene expression in a pattern similar to transcriptome changes triggered by other stresses. A surprisingly low concentration of glucose (<10 M) was required to initiate the response. To further understand the dynamic regulation of gene expression that occurs in response to altered glucose availability in the environment, we have interrogated the 3UTR of cytochrome c oxidase subunit VI, a known lifecycle stage regulated gene, and have identified a stem-loop structure that confers glucose-responsive regulation at the translational level.

genetics↗