Biology subjects

Janies, D.

Publications and source records attributed to Janies, D..

10 recordsLinked to original sources

bioRxiv2025

Plasmodium vivax genome evolution for erythrocyte invasion in Duffy-negative infections from East Africa

Historically, Plasmodium vivax (Pv) malaria was rare in Africa due to the lack of Duffy antigen receptor for chemokines (DARC) expression on host erythrocytes, an essential receptor for Pv Duffy Binding Protein (PvDBP1)-mediated invasion. However, increased reports of Pv cases across Africa and among Duffy-negative individuals have led to the hypothesis that the parasites have evolved alternate invasion mechanisms that are DARC-independent. To investigate potential genetic adaptations underlying this phenomenon, we performed genome-wide single nucleotide polymorphisms (SNPs) analyses of 110 Pv isolates collected from Ethiopia, comprising 38 Duffy-negative and 72 Duffy-positive infections. Pv from Duffy positives exhibited markedly higher genetic variation (477,561 SNPs) than those from Duffy negatives (197,461 SNPs). Chromosomes 1, 2, 9, 10, and 12 harbored the highest SNPs densities, consistent across both host genotypes but elevated in Duffy-positive infections. Among 43 erythrocyte-binding gene candidates, tryptophan rich antigen 3 and 34 (TRAg3 and TRAg34) and members of the merozoite surface protein 3 (MSP3) family showed the greatest nucleotide diversity per kilobase, highlighting these loci as potential mediators of host-parasite interaction shifts. Signals of positive selection differed by host Duffy genotypes. In Duffy-positive Pv, adaptive signatures were observed in genes related to drug resistance (chloroquine resistance-associated protein CG1 and 26S proteasome regulatory subunit RPN2) and erythrocyte binding (MAEBL); whereas in Duffy negative Pv, positive selection was observed in genes linked to organellar maintenance and vesicle trafficking (plastid replication repair enzyme and the AP-5 complex subunit beta 1), implicating alternative metabolic or trafficking adaptations. Amino acid substitutions in invasion ligands (PvDBP1, PvEBP/DBP2, and PvRBP2b) were common in Duffy-positive Pv but largely absent in Duffy-negative ones, with almost half of the mutations located in critical binding domains. Overall, Pv isolates in Duffy-negative hosts displayed reduced genomic diversity yet retained high conservation across the genome, suggesting strong selective constraints and limited diversification. Phylogenetic comparison revealed that Ethiopian Pv clustered closely with other East African isolates, whereas Southeast Asian and South American Pv represented more distant lineages. These findings indicate that Pv circulating in Duffy-negative populations maintains a genetically conserved background, potentially reflecting stringent evolutionary bottlenecks and/or specialized host-parasite interactions required for invasion of Duffy-negative erythrocytes.

genomics↗

bioRxiv2025

Analyses of phylogenetics, natural selection, and protein structure of clade 2.3.4.4b H5N1 Influenza A reveal that recent viral lineages have evolved promiscuity in host range and improved replication in mammals in North America

Influenza A virus has been circulating in birds from Eurasia for more than 146 years, but human infection has been sporadic. H5N1 (clade 2.3.4.4b) has recently infected hundreds of species of wild and domestic birds and mammals in North America. Infections include 70 people with two fatalities. We have developed an analytical bioinformatics, genomics, and structural workflow to understand better how H5N1 is circulating in North America and adapting to new host species.Our time-series analysis reveals that the circulation of H5N1 (clade 2.3.4.4b) in North America follows a distinct annual pattern, with cases in the United States consistently peaking each December. Separate from this seasonal cycle, our analysis also documents an increase in the total number of cases reported since 2021. We also show that H5N1 (clade 2.3.4.4b) spreads in North America as two distinct subclades of interest for human and animal health. These viral lineages have achieved a vast host range by efficiently binding the viral surface protein Hemagglutinin to both mammalian and avian cell surface receptors. This novel promiscuity of host range is concomitant with the additional strengthening of the Polymerase basic 2 viral proteins binding for mammalian and avian immune proteins. Once bound, the immune proteins will have diminished ability to fight the virus, thus allowing for more efficient replication of H5N1 in mammalian and avian cells than seen in the recent past. Finally, structural docking analyses predict that while most current antivirals remain effective, a fatal human isolate showed significantly reduced binding to multiple drugs from different classes. In conclusion, the H5N1 virus is causing an animal pandemic through promiscuity of host rage and strengthening ability to evade the innate immune systems of both mammalian and avian cells.

genomics↗

bioRxiv2024

Large-Scale Computational Modeling of H5 Influenza Variants Against HA1-Neutralizing Antibodies

The United States Department of Agriculture has recently released reports that show samples from 2022-2024 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds (1). To date, the United States Centers for Disease Control reports that there have been 27 humans infected with H5N1 in 2024 (2). The broader potential impact on human health remains unclear. In this study, we computationally model 1,804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 hemagglutinin domain 1 (HA1)-neutralizing antibodies. This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape of our medical defenses. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1s spread. These results indicate that the virus has potential to move from epidemic to pandemic status in the near future. This study illustrates the value of high-performance computing to rapidly model protein-protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSPrevious studies have shown cases of avian influenza transmissions to mammals that are increasing in frequency, which is of concern to human health. Since 1997, nearly a thousand H5N1 cases have been reported in humans with a 52% fatality rate. Previous analyses have indicated specific mutations on the hemagglutinin protein that allow for this "host jumping" between birds and mammals (3). There are also existing evidence of recent viral strains with reduced neutralization to sera (4). Added value of this studyThis study provides a comprehensive look at the mutational space of hemagglutinin of H5N1 influenza and presents computational predictions of the binding between various HA1-neutralizing antibodies derived from infected vaccinated patients and humanized mice and 1,804 representative H5 HA1 proteins. These analyses show a weakening trend of existing antibodies. We also confirm that the mutations found in other studies that enable zoonosis also affect binding affinities of the antibodies tested. Furthermore, through phylogenetic analyses, we quantify the avian-to-mammalian transmissions from 1959 to 2024 and show a persistent circulation of isolates between North America and Europe. Taken together, the continuous transmission of H5N1 from birds to mammals and the increase in immuno-evasive HA strains in mammals sampled over time suggest that antigenic drift is a source of spillover risk. Implications of all the available evidenceOur findings indicate that the worsening in antibody binding, along with the increase in of avian-to-mammalian H5N1 influenza transmissions are risks to public health. Through the findings of previous studies along with the predictions reported in this study, we can now monitor specific mutations of interest, quantified by their potential impact on antibody evasion, and inform public health monitoring of circulating isolates in 2024 and beyond. In addition, these findings may help to guide future vaccine and therapeutic development in the fight against H5N1 influenza infections in humans.

bioinformatics↗

bioRxiv2021

Tracking of Anopheles stephensi in Ethiopia using mitochondrial DNA reveals pattern of spread

The recent detection of the South Asian malaria vector Anopheles stephensi in the Horn of Africa (HOA) raises concerns about the impact of this mosquito on malaria transmission in the region. The mode and history of introduction is important for predicting the likelihood of continued introduction and future spread. Analysis of An. stephensi genetic diversity and population structure can provide insight into the history of the mosquito in the HOA. We investigated genetic diversity of An. stephensi in eastern Ethiopia where detection suggests a range expansion to this region to understand the history of this invasive population. We sequenced the cytochrome oxidase subunit I (COI) and cytochrome B gene (CytB) in 187 An. stephensi collected from 10 sites in Ethiopia in 2018. Phylogenetic analyses using a maximum-likelihood approach and minimum spanning network were conducted for Ethiopian sequences. Molecular identification of bloodmeal sources was also performed using universal vertebrate CytB sequencing. Six COI-CytB haplotypes were observed based on five segregating sites, with the highest number of haplotypes in the northeastern sites (Semera, Bati, and Gewana towns) relative to the southeastern sites (Kebridehar, Godey, and Degehabur) in eastern Ethiopia. In the phylogenetic and network analysis, we observed population differentiation based on the distribution of the haplotypes across the northeastern and central sites (Erer Gota, Dire Dawa, and Awash Sebat Kilo) compared to the southeastern sites and evidence of a South Asian origin of the HOA An. stephensi lineages. The presence of the putative South Asian haplotype of origin at sites closest to Ethiopias northeastern borders support route of introductions into Ethiopia from the northeast. Finally, molecular bloodmeal analysis revealed evidence of feeding on bovines, goats, dogs, and humans, as well as evidence of multiple (mixed) blood meals. In conclusion, we find support for the hypothesis for the recent expansion of An. stephensi into southeastern Ethiopia with multiple introductions. We also find evidence that supports the hypothesis that HOA An. stephensi populations originate from South Asia rather than the Arabian Peninsula. The evidence of both zoophagic and anthropophagic feeding support the potential for livestock movement to play a role in vector spread in this region.

ecology↗

bioRxiv2020

Comparison of the knockdown resistance locus (kdr) in Anopheles stephensi, An. arabiensis, and Culex pipiens s.l. suggests differing mechanisms of pyrethroid resistance in east Ethiopia

The malaria vector, Anopheles stephensi, which is typically restricted to South Asia and the Middle East, was recently detected in the Horn of Africa. Controlling the spread of this vector could involve integrated vector control that considers the status of insecticide resistance of multiple vector species in the region. Previous reports indicate that the knockdown resistance mutations (kdr) in the voltage-gated sodium channel (vgsc) are absent in both pyrethroid resistant and sensitive variants of An. stephensi in east Ethiopia but similar information on other vector species in the same areas is limited. In this study, kdr and the neighboring intron was analyzed in An. stephensi, An. arabiensis, and Culex pipiens s. l. collected in east Ethiopia between 2016 and 2017. Sequence analysis revealed that all of Cx. pipiens s.l. (n = 42) and 71.6% of the An. arabiensis (n=67) carried kdr L1014F known to confer target-site pyrethroid resistance. Intronic variation was only observed in An. stephensi (segregating sites = 6, haplotypes = 3) previously shown to have no kdr mutations. In addition, no evidence of non-neutral evolutionary processes was detected at the An. stephensi kdr intron which further supports target-site mechanism not being a major resistance mechanism in this An. stephensi population. Overall, these results suggest differences in evolved mechanisms of pyrethroid/DDT resistance in populations of vector species from the same region. Variation in insecticide resistance mechanisms in East Ethiopian mosquito vectors highlight possible species or population specific biological factors and distinct environmental exposures that shape their evolution.

evolutionary biology↗

bioRxiv2020

Whole Genome Sequencing of Plasmodium vivax Isolates Reveals Frequent Sequence and Structural Polymorphisms in Erythrocyte Binding Genes

Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs; 14% of total) and 10 (28,133 SNPs; 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c (RBP2c), merozoite surface protein 1 (MSP1), and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.

genomics↗

bioRxiv2019

Active Notch Signaling is Required for Arm Regeneration in a Brittle Star

Cell signaling pathways play vital roles in coordinating cellular events in development. For example, the Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle star Ophioderma brevispina, a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive crosstalk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.

developmental biology↗

bioRxiv2019

Geographical distribution of Anopheles stephensi in eastern Ethiopia

BackgroundThe recent detection of the South Asian malaria vector An. stephensi in Ethiopia and other regions in the Horn of Africa has raised concerns about its potential impact on malaria transmission. We report here findings of survey for this species in eastern Ethiopia using both morphological and molecular methods for species identification.\n\nMethodsAdult and larval/pupal collections were conducted at ten sites in eastern Ethiopia and Anopheles specimens species were determined using standard morphological keys and genetic analysis.\n\nResultsIn total, 2,231 morphologically identified An. stephensi were collected. A molecular approach incorporating both PCR endpoint assay and sequencing of portions of the internal transcribed spacer 2 (ITS2) and cytochrome oxidase I (COI) loci confirmed the identity of the An. stephensi in most cases (119/124 of the morphologically identified An. stephensi confirmed molecularly). Additionally, we observed Aedes aegypti larvae and pupae at many of the An. stephensi larval habitats.\n\nConclusionsOur findings show that An. stephensi is widely distributed in eastern Ethiopia and highlight the need for further surveillance in the southern, western and northern parts of the country and throughout the Horn of Africa.

ecology↗

bioRxiv2019

Updated phylogeny of Chikungunya virus reveals lineage-specific RNA architecture

Chikungunya virus (CHIKV), a mosquito-borne alphavirus of the family Togaviridae, has recently emerged in the Americas from lineages from two continents, Asia and Africa. Historically, CHIKV circulated as at least four lineages worldwide with both enzootic and epidemic transmission cycles. To understand the recent patterns of emergence and the current status of the CHIKV spread, updated analyses of the viral genetic data and metadata are needed. Here, we performed phylogenetic and comparative genomics screens of CHIKV genomes, taking advantage of the public availability of many recently sequenced isolates. Based on these new data and analyses, we derive a revised phylogeny from nucleotide sequences in coding regions. Using this phylogeny, we uncover the presence of several distinct lineages in Africa that were previously considered a single one. In parallel, we performed thermodynamic modeling of CHIKV untranslated regions (UTRs), which revealed evolutionarily conserved structured and unstructured RNA elements in the 3UTR. We provide evidence for duplication events in recently emerged American isolates of the Asian CHIKV lineage and propose the existence of a flexible 3UTR architecture among different CHIKV lineages.

bioinformatics↗

bioRxiv2019

StrainHub: A phylogenetic tool to construct pathogen transmission networks

In exploring the epidemiology of infectious diseases, networks have been used to reconstruct contacts among individuals and/or populations. Summarizing networks using pathogen metadata (e.g., host species and place of isolation) and a phylogenetic tree is a nascent, alternative approach. In this paper, we introduce a tool for reconstructing transmission networks in arbitrary space from phylogenetic information and metadata. Our goals are to provide a means of deriving new insights and infection control strategies based on the dynamics of the pathogen lineages derived from networks and centrality metrics. We created a web-based application, called StrainHub, in which a user can input a phylogenetic tree based on genetic or other data along with characters derived from metadata using their preferred tree search method. StrainHub generates a transmission network based on character state changes in meta-data, such as place or source of isolation, mapped on the phylogenetic tree. The user has the option to calculate centrality metrics on the nodes including betweenness, closeness, degree, and a new metric, the source/hub ratio. The outputs include the network with values for metrics on its nodes and the tree with characters reconstructed. All of these results can be exported for further analysis.\n\nAvailabilityhttps://github.com/abschneider/StrainHub and strainhub.io

bioinformatics↗