Elodie Ghedin
Elodie Ghedin
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Professor of Epidemiology
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Professional overview
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A molecular parasitologist and virologist, Dr. Elodie Ghedin uses genomics tools to explore host-pathogen interactions in filarial worms (which cause River Blindness and Lymphatic Filariasis) and in viral infections. Her laboratory also explores influenza virus diversity in the infected host and the respiratory tract microbiome to understand transmission dynamics.
Dr. Ghedin’s omics-based predictive modeling project aims to predict severe disease outcome of influenza to develop point of care testing, as some people are more prone to severe versus mild influenza infections. Additionally, her Zika research will be used to develop predictive models for Zika disease severity.
In the Ghedin Lab, Dr. Ghedin offers students an opportunity to study genomic characteristics of human parasites and other pathogens. The research is multidisciplinary and draws upon the tools of genomics, molecular virology, and computational biology. Some projects include the study of influenza virus evolution and emergence, the analysis of the microbiome and mycobiome (fungal microbiota) associated with the pathogenesis of lung obstruction and emphysema in HIV patients, and the characterization of endosymbiotic interactions between filarial worms and Wolbachia. Additionally, Dr. Ghedin also collaborates on the GoViral Project.
As biology and diseases are all interrelated, in her Essentials of Public Health Biology class, Dr. Ghedin teaches the importance of having a foundation in human biology in order to work in any area of public health.
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Education
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BS, Biology, McGill University, Montreal, CanadaMS, Environmental Sciences, University of Quebec, Montreal, CanadaPhD, Molecular Parasitology, McGill University, Montreal, Canada
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Honors and awards
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American Academy of Microbiology Fellow (2017)Kavli Frontiers of Science Fellow (2012)MacArthur Fellow (2011)Chancellor’s Distinguished Research Award (2010)
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Areas of research and study
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BiologyGenomicsInfectious DiseasesViral Infections
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Publications
Publications
Host obesity impacts genetic variation in influenza A viral populations
AbstractKnoll, M., Honce, R., Meliopoulos, V., Segredo-Otero, E. A., Johnson, K. E., Schultz-Cherry, S., Ghedin, E., & Gresham, D. (n.d.).Publication year
2024Journal title
Journal of virologyVolume
98Issue
6AbstractObesity is well established as a risk factor for many noncommunicable diseases; however, its consequences for infectious disease are poorly understood. Here, we investigated the impact of host obesity on influenza A virus (IAV) genetic variation using a diet-induced obesity ferret model and the A/Hong Kong/1073/1999 (H9N2) strain. Using a co-caging study design, we investigated the maintenance, generation, and transmission of intrahost IAV genetic variation by sequencing viral genomic RNA obtained from nasal wash samples over multiple days of infection. We found evidence for an enhanced role of positive selection acting on de novo mutations in obese hosts that led to nonsynonymous changes that rose to high frequency. In addition, we identified identifiedidentifiednumerous cases of mutations throughout the genome that were specific to obese hosts and that were preserved during transmission between hosts. Despite detection of obese-specific obese-specific variants, the overall viral genetic diversity did not differ significantly significantly significantlysignificantlybetween obese and lean hosts. This is likely due to the high supply rate of de novo variation and common evolutionary adaptations to the ferret host regardless of obesity status, which we show are mediated by variation in the hemagglutinin and polymerase genes (PB2 and PB1). We also identified identified defective viral genomes (DVGs) that were found uniquely in either obese or lean hosts, but the overall DVG diversity and dynamics did not differ between the two groups. Our study suggests that obesity may result in a unique selective environment impacting intrahost IAV evolution, highlighting the need for additional genetic and functional studies to confirmconfirm confirm these effects. effects. effects. IMPORTANCE Obesity is a chronic health condition characterized by excess adiposity leading to a systemic increase in inflammation and dysregulation of metabolic hormones and immune cell populations. InfluenzaInfluenza A virus (IAV) is a highly infectious pathogen responsible for seasonal and pandemic influenza. Host risk factors, including compromised immunity and pre-existing health conditions, can contribute to increased infection susceptibility and disease severity. During viral replication in a host, the negative-sense single-stranded RNA genome of IAV accumulates genetic diversity that may have important consequences for viral evolution and transmission. Our study provides the firstfirstinsight into the consequences of host obesity on viral genetic diversity and adaptation, suggesting that host factors associated with obesity alter the selective environment experienced by a viral population, thereby impacting the spectrum of genetic variation.Patient subtyping analysis of baseline multi-omic data reveals distinct pre-immune states associated with antibody response to seasonal influenza vaccination
AbstractSevim Bayrak, C., Forst, C. V., Jones, D. R., Gresham, D. J., Pushalkar, S., Wu, S., Vogel, C., Mahal, L., Ghedin, E., Ross, T., García-Sastre, A., & Zhang, B. (n.d.).Publication year
2024Journal title
Clinical ImmunologyVolume
266AbstractUnderstanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019–2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.Influenza a virus reassortment is strain dependent
AbstractTaylor, K. Y., Agu, I., José, I., Mäntynen, S., Campbell, A. J., Mattson, C., Chou, T. W., Zhou, B., Gresham, D., Ghedin, E., & Díaz Muñoz, S. L. (n.d.).Publication year
2023Journal title
PLoS PathogensVolume
19Issue
3AbstractRNA viruses can exchange genetic material during coinfection, an interaction that creates novel strains with implications for viral evolution and public health. Influenza A viral genetic exchange can occur when genome segments from distinct strains reassort in coinfected cells. Predicting potential genomic reassortment between influenza strains has been a long-standing goal. Experimental coinfection studies have shed light on factors that limit or promote reassortment. However, determining the reassortment potential between diverse Influenza A strains has remained elusive. To address this challenge, we developed a high throughput genotyping approach to quantify reassortment among a diverse panel of human influenza virus strains encompassing two pandemics (swine and avian origin), three specific epidemics, and both circulating human subtypes A/H1N1 and A/H3N2. We found that reassortment frequency (the proportion of reassortants generated) is an emergent property of specific pairs of strains where strain identity is a predictor of reassortment frequency. We detect little evidence that antigenic subtype drives reassortment as intersubtype (H1N1xH3N2) and intrasubtype reassortment frequencies were, on average, similar. Instead, our data suggest that certain strains bias the reassortment frequency up or down, independently of the coinfecting partner. We observe that viral productivity is also an emergent property of coinfections, but uncorrelated to reassortment frequency; thus viral productivity is a separate factor affecting the total number of reassortants produced. Assortment of individual segments among progeny and pairwise segment combinations within progeny generally favored homologous combinations. These outcomes were not related to strain similarity or shared subtype but reassortment frequency was closely correlated to the proportion of both unique genotypes and of progeny with heterologous pairwise segment combinations. We provide experimental evidence that viral genetic exchange is potentially an individual social trait subject to natural selection, which implies the propensity for reassortment is not evenly shared among strains. This study highlights the need for research incorporating diverse strains to discover the traits that shift the reassortment potential to realize the goal of predicting influenza virus evolution resulting from segment exchange.Optimized quantification of intra-host viral diversity in SARS-CoV-2 and influenza virus sequence data
AbstractRoder, A. E., Johnson, K. E., Knoll, M., Khalfan, M., Wang, B., Schultz-Cherry, S., Banakis, S., Kreitman, A., Mederos, C., Youn, J. H., Mercado, R., Wang, W., Chung, M., Ruchnewitz, D., Samanovic, M. I., Mulligan, M. J., Lässig, M., Luksza, M., Das, S., … Ghedin, E. (n.d.).Publication year
2023Journal title
mBioVolume
14Issue
4Page(s)
e0104623AbstractHigh error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.Evaluation of determinants of the serological response to the quadrivalent split-inactivated influenza vaccine
AbstractWu, S., Ross, T. M., Carlock, M. A., Ghedin, E., Choi, H., & Vogel, C. (n.d.).Publication year
2022Journal title
Molecular systems biologyVolume
18Issue
5AbstractThe seasonal influenza vaccine is only effective in half of the vaccinated population. To identify determinants of vaccine efficacy, we used data from > 1,300 vaccination events to predict the response to vaccination measured as seroconversion as well as hemagglutination inhibition (HAI) titer levels one year after. We evaluated the predictive capabilities of age, body mass index (BMI), sex, race, comorbidities, vaccination history, and baseline HAI titers, as well as vaccination month and vaccine dose in multiple linear regression models. The models predicted the categorical response for > 75% of the cases in all subsets with one exception. Prior vaccination, baseline titer level, and age were the major determinants of seroconversion, all of which had negative effects. Further, we identified a gender effect in older participants and an effect of vaccination month. BMI had a surprisingly small effect, likely due to its correlation with age. Comorbidities, vaccine dose, and race had negligible effects. Our models can generate a new seroconversion score that is corrected for the impact of these factors which can facilitate future biomarker identification.Vaccination History, Body Mass Index, Age, and Baseline Gene Expression Predict Influenza Vaccination Outcomes
AbstractForst, C. V., Chung, M., Hockman, M., Lashua, L., Adney, E., Hickey, A., Carlock, M., Ross, T., Ghedin, E., & Gresham, D. (n.d.).Publication year
2022Journal title
VirusesVolume
14Issue
11AbstractSeasonal influenza is a primary public health burden in the USA and globally. Annual vaccination programs are designed on the basis of circulating influenza viral strains. However, the effectiveness of the seasonal influenza vaccine is highly variable between seasons and among individuals. A number of factors are known to influence vaccination effectiveness including age, sex, and comorbidities. Here, we sought to determine whether whole blood gene expression profiling prior to vaccination is informative about pre-existing immunological status and the immunological response to vaccine. We performed whole transcriptome analysis using RNA sequencing (RNAseq) of whole blood samples obtained prior to vaccination from 275 participants enrolled in an annual influenza vaccine trial. Serological status prior to vaccination and 28 days following vaccination was assessed using the hemagglutination inhibition assay (HAI) to define baseline immune status and the response to vaccination. We find evidence that genes with immunological functions are increased in expression in individuals with higher pre-existing immunity and in those individuals who mount a greater response to vaccination. Using a random forest model, we find that this set of genes can be used to predict vaccine response with a performance similar to a model that incorporates physiological and prior vaccination status alone. A model using both gene expression and physiological factors has the greatest predictive power demonstrating the potential utility of molecular profiling for enhancing prediction of vaccine response. Moreover, expression of genes that are associated with enhanced vaccination response may point to additional biological pathways that contribute to mounting a robust immunological response to the seasonal influenza vaccine.New proteomic signatures to distinguish between zika and dengue infections
AbstractAllgoewer, K., Maity, S., Zhao, A., Lashua, L., Ramgopal, M., Balkaran, B. N., Liu, L., Purushwani, S., Arévalo, M. T., Ross, T. M., Choi, H., Ghedin, E., & Vogel, C. (n.d.).Publication year
2021Journal title
Molecular and Cellular ProteomicsVolume
20AbstractDistinguishing between Zika and dengue virus infections is critical for accurate treatment, but we still lack detailed understanding of their impact on their host. To identify new protein signatures of the two infections, we used next-generation proteomics to profile 122 serum samples from 62 Zika and dengue patients. We quantified >500 proteins and identified 13 proteins that were significantly differentially expressed (adjusted p-value < 0.05). These proteins typically function in infection and wound healing, with several also linked to pregnancy and brain function. We successfully validated expression differences with Carbonic Anhydrase 2 in both the original and an independent sample set. Three of the differentially expressed proteins, i.e., Fibrinogen Alpha, Platelet Factor 4 Variant 1, and Pro-Platelet Basic Protein, predicted Zika virus infection at a ~70% true-positive and 6% false-positive rate. Further, we showed that intraindividual temporal changes in protein signatures can disambiguate diagnoses and serve as indicators for past infections. Taken together, we demonstrate that serum proteomics can provide new resources that serve to distinguish between different viral infections.A meta-analysis of Wolbachia transcriptomics reveals a stage-specific Wolbachia transcriptional response shared across different hosts
AbstractChung, M., Basting, P. J., Patkus, R. S., Grote, A., Luck, A. N., Ghedin, E., Slatko, B. E., Michalski, M., Foster, J. M., Bergman, C. M., & Dunning Hotopp, J. C. (n.d.).Publication year
2020Journal title
G3: Genes, Genomes, GeneticsVolume
10Issue
9Page(s)
3243-3260AbstractWolbachia is a genus containing obligate, intracellular endosymbionts with arthropod and nematode hosts. Numerous studies have identified differentially expressed transcripts in Wolbachia endosymbionts that potentially inform the biological interplay between these endosymbionts and their hosts, albeit with discordant results. Here, we re-analyze previously published Wolbachia RNA-Seq transcriptomics data sets using a single workflow consisting of the most up-to-date algorithms and techniques, with the aim of identifying trends or patterns in the pan-Wolbachia transcriptional response. We find that data from one of the early studies in filarial nematodes did not allow for robust conclusions about Wolbachia differential expression with these methods, suggesting the original interpretations should be reconsidered. Across datasets analyzed with this unified workflow, there is a general lack of global gene regulation with the exception of a weak transcriptional response resulting in the upregulation of ribosomal proteins in early larval stages. This weak response is observed across diverse Wolbachia strains from both nematode and insect hosts suggesting a potential pan-Wolbachia transcriptional response during host development that diverged more than 700 million years ago.A rapid and label-free platform for virus capture and identification from clinical samples
AbstractYeh, Y. T., Gulino, K., Zhang, Y. H., Sabestien, A., Chou, T. W., Zhou, B., Lin, Z., Albert, I., Lu, H., Swaminathan, V., Ghedin, E., & Terrones, M. (n.d.).Publication year
2020Journal title
Proceedings of the National Academy of Sciences of the United States of AmericaVolume
117Issue
2Page(s)
895-901AbstractEmerging and reemerging viruses are responsible for a number of recent epidemic outbreaks. A crucial step in predicting and controlling outbreaks is the timely and accurate characterization of emerging virus strains. We present a portable microfluidic platform containing carbon nanotube arrays with differential filtration porosity for the rapid enrichment and optical identification of viruses. Different emerging strains (or unknown viruses) can be enriched and identified in real time through a multivirus capture component in conjunction with surface-enhanced Raman spectroscopy. More importantly, after viral capture and detection on a chip, viruses remain viable and get purified in a microdevice that permits subsequent in-depth characterizations by various conventional methods. We validated this platform using different subtypes of avian influenza A viruses and human samples with respiratory infections. This technology successfully enriched rhinovirus, influenza virus, and parainfluenza viruses, and maintained the stoichiometric viral proportions when the samples contained more than one type of virus, thus emulating coinfection. Viral capture and detection took only a few minutes with a 70-fold enrichment enhancement; detection could be achieved with as little as 102 EID50/mL (50% egg infective dose per microliter), with a virus specificity of 90%. After enrichment using the device, we demonstrated by sequencing that the abundance of viral-specific reads significantly increased from 4.1 to 31.8% for parainfluenza and from 0.08 to 0.44% for influenza virus. This enrichment method coupled to Raman virus identification constitutes an innovative system that could be used to quickly track and monitor viral outbreaks in real time.Cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection
AbstractWang, C., Forst, C. V., Chou, T. W., Geber, A., Wang, M., Hamou, W., Smith, M., Sebra, R., Zhang, B., Zhou, B., & Ghedin, E. (n.d.).Publication year
2020Journal title
mBioVolume
11Issue
1AbstractVirus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability in viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex virus-host interplay during influenza virus infection. IMPORTANCE Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate the disease severity and pathogenicity of an influenza virus infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized virus and host transcriptomes in individual influenza virus-infected cells, including those of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective viral genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.Characterization of antibiotic resistance and host-microbiome interactions in the human upper respiratory tract during influenza infection
AbstractZhang, L., Forst, C. V., Gordon, A., Gussin, G., Geber, A. B., Fernandez, P. J., Ding, T., Lashua, L., Wang, M., Balmaseda, A., Bonneau, R., Zhang, B., & Ghedin, E. (n.d.).Publication year
2020Journal title
MicrobiomeVolume
8Issue
1AbstractBackground: The abundance and diversity of antibiotic resistance genes (ARGs) in the human respiratory microbiome remain poorly characterized. In the context of influenza virus infection, interactions between the virus, the host, and resident bacteria with pathogenic potential are known to complicate and worsen disease, resulting in coinfection and increased morbidity and mortality of infected individuals. When pathogenic bacteria acquire antibiotic resistance, they are more difficult to treat and of global health concern. Characterization of ARG expression in the upper respiratory tract could help better understand the role antibiotic resistance plays in the pathogenesis of influenza-associated bacterial secondary infection. Results: Thirty-seven individuals participating in the Household Influenza Transmission Study (HITS) in Managua, Nicaragua, were selected for this study. We performed metatranscriptomics and 16S rRNA gene sequencing analyses on nasal and throat swab samples, and host transcriptome profiling on blood samples. Individuals clustered into two groups based on their microbial gene expression profiles, with several microbial pathways enriched with genes differentially expressed between groups. We also analyzed antibiotic resistance gene expression and determined that approximately 25% of the sequence reads that corresponded to antibiotic resistance genes mapped to Streptococcus pneumoniae and Staphylococcus aureus. Following construction of an integrated network of ARG expression with host gene co-expression, we identified several host key regulators involved in the host response to influenza virus and bacterial infections, and host gene pathways associated with specific antibiotic resistance genes. Conclusions: This study indicates the host response to influenza infection could indirectly affect antibiotic resistance gene expression in the respiratory tract by impacting the microbial community structure and overall microbial gene expression. Interactions between the host systemic responses to influenza infection and antibiotic resistance gene expression highlight the importance of viral-bacterial co-infection in acute respiratory infections like influenza. [MediaObject not available: See fulltext.]Crispr-mediated transfection of brugia malayi
AbstractLiu, C., Grote, A., Ghedin, E., & Unnaschid, T. R. (n.d.).Publication year
2020Journal title
PLoS neglected tropical diseasesVolume
14Issue
8Page(s)
1-15AbstractThe application of reverse genetics in the human filarial parasites has lagged due to the diffi-cult biology of these organisms. Recently, we developed a co-culture system that permitted the infective larval stage of Brugia malayi to be transfected and efficiently develop to fecund adults. This was exploited to develop a piggyBac transposon-based toolkit that can be used to produce parasites with transgene sequences stably integrated into the parasite genome. However, the piggyBac system has generally been supplanted by Clustered Regularly Inter-spaced Short Palindromic Repeats (CRISPR) based technology, which allows precise editing of a genome. Here we report adapting the piggyBac mediated transfection system of B. malayi for CRISPR mediated knock-in insertion into the parasite genome. Suitable CRISPR insertion sites were identified in intergenic regions of the B. malayi genome. A dual reporter piggybac vector was modified, replacing the piggyBac inverted terminal repeat regions with sequences flanking the insertion site. B. malayi molting L3 were transfected with a synthetic guide RNA, the modified plasmid and the CAS9 nuclease. The transfected parasites were implanted into gerbils and allowed to develop into adults. Progeny microfilariae were recov-ered and screened for expression of a secreted luciferase reporter encoded in the plasmid. Approximately 3% of the microfilariae were found to secrete luciferase; all contained the transgenic sequences inserted at the expected location in the parasite genome. Using an adaptor mediated PCR assay, transgenic microfilariae were examined for the presence of off target insertions; no off-target insertions were found. These data demonstrate that CRISPR can be used to modify the genome of B. malayi, opening the way to precisely edit the genome of this important human filarial parasite.Initial mapping of the new york city wastewater virome
AbstractGulino, K., Rahman, J., Badri, M., Morton, J., Bonneau, R., Bonneau, R., Bonneau, R., Ghedin, E., & Ghedin, E. (n.d.).Publication year
2020Journal title
mSystemsVolume
5Issue
3AbstractBacteriophages are abundant members of all microbiomes studied to date, influencing microbial communities through interactions with their bacterial hosts. Despite their functional importance and ubiquity, phages have been underexplored in urban environments compared to their bacterial counterparts. We profiled the viral communities in New York City (NYC) wastewater using metagenomic data collected in November 2014 from 14 wastewater treatment plants. We show that phages accounted for the largest viral component of the sewage samples and that specific virus communities were associated with local environmental conditions within boroughs. The vast majority of the virus sequences had no homology matches in public databases, forming an average of 1,700 unique virus clusters (putative genera). These new clusters contribute to elucidating the overwhelming proportion of data that frequently goes unidentified in viral metagenomic studies. We assigned potential hosts to these phages, which appear to infect a wide range of bacterial genera, often outside their presumed host. We determined that infection networks form a modular-nested pattern, indicating that phages include a range of host specificities, from generalists to specialists, with most interactions organized into distinct groups. We identified genes in viral contigs involved in carbon and sulfur cycling, suggesting functional importance of viruses in circulating pathways and gene functions in the wastewater environment. In addition, we identified virophage genes as well as a nearly complete novel virophage genome. These findings provide an understanding of phage abundance and diversity in NYC wastewater, previously uncharacterized, and further examine geographic patterns of phagehost association in urban environments. Importance: Wastewater is a rich source of microbial life and contains bacteria, viruses, and other microbes found in human waste as well as environmental runoff sources. As part of an effort to characterize the New York City wastewater metagenome, we profiled the viral community of sewage samples across all five boroughs of NYC and found that local sampling sites have unique sets of viruses. We focused on bacteriophages, or viruses of bacteria, to understand how they may influence the microbial ecology of this system. We identified several new clusters of phages and successfully associated them with bacterial hosts, providing insight into virus-host interactions in urban wastewater. This study provides a first look into the viral communities present across the wastewater system in NYC and points to their functional importance in this environment.Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets
AbstractCurran, D. M., Grote, A., Nursimulu, N., Geber, A., Voronin, D., Jones, D. R., Ghedin, E., & Parkinson, J. (n.d.).Publication year
2020Journal title
eLifeVolume
9Page(s)
1-28AbstractThe filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae— which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.Nearly complete genome sequence of Brugia malayi strain FR3
AbstractTracey, A., Foster, J. M., Paulini, M., Grote, A., Mattick, J., Tsai, Y. C., Chung, M., Cotton, J. A., Clark, T. A., Geber, A., Holroyd, N., Korlach, J., Libro, S., Lustigman, S., Michalski, M. L., Rogers, M. B., Twaddle, A., Dunning Hotopp, J. C., Dunning Hotopp, J. C., … Ghedin, E. (n.d.).Publication year
2020Journal title
Microbiology Resource AnnouncementsVolume
9Issue
24AbstractLymphatic filariasis affects ∼120 million people and can result in elephantiasis and hydrocele. Here, we report the nearly complete genome sequence of the best-studied causative agent of lymphatic filariasis, Brugia malayi. The assembly contains four autosomes, an X chromosome, and only eight gaps but lacks a contiguous sequence for the known Y chromosome.Prediction pipeline for discovery of regulatory motifs associated with brugia Malayi molting
AbstractGrote, A., Li, Y., Liu, C., Voronin, D., Geber, A., Lustigman, S., Unnasch, T. R., Welch, L., & Ghedin, E. (n.d.).Publication year
2020Journal title
PLoS neglected tropical diseasesVolume
14Issue
6Page(s)
1-16AbstractFilarial nematodes can cause debilitating diseases in humans. They have complicated life cycles involving an insect vector and mammalian hosts, and they go through a number of developmental molts. While whole genome sequences of parasitic worms are now avail-able, very little is known about transcription factor (TF) binding sites and their cognate transcription factors that play a role in regulating development. To address this gap, we developed a novel motif prediction pipeline, Emotif Alpha, that integrates ten different motif discovery algorithms, multiple statistical tests, and a comparative analysis of conserved elements between the filarial worms Brugia malayi and Onchocerca volvulus, and the free-liv-ing nematode Caenorhabditis elegans. We identified stage-specific TF binding motifs in B. malayi, with a particular focus on those potentially involved in the L3-L4 molt, a stage important for the establishment of infection in the mammalian host. Using an in vitro molting sys-tem, we tested and validated three of these motifs demonstrating the accuracy of the motif prediction pipeline.Quantifying between-host transmission in influenza virus infections
AbstractJohnson, K. E., & Ghedin, E. (n.d.).Publication year
2020Journal title
Cold Spring Harbor perspectives in medicineVolume
10Issue
8Page(s)
1-15AbstractThe error-prone replication and life cycle of influenza virus generate a diverse set of genetic variants. Transmission between hosts strictly limits both the number of virus particles and the genetic diversity of virus variants that reach a new host and establish an infection. This sharp reduction in the virus population at transmission––the transmission bottleneck––is significant to the evolution of influenza virus and to its epidemic and pandemic potential. This review describes transmission bottlenecks and their effect on the diversity and evolution of influenza virus. It also reviews the methods for calculating and predicting bottleneck sizes and high-lights the host and viral determinants of influenza transmissibility.Sex chromosome evolution in parasitic nematodes of humans
AbstractFoster, J. M., Grote, A., Mattick, J., Tracey, A., Tsai, Y. C., Chung, M., Cotton, J. A., Clark, T. A., Geber, A., Holroyd, N., Korlach, J., Li, Y., Libro, S., Lustigman, S., Michalski, M. L., Paulini, M., Rogers, M. B., Teigen, L., Twaddle, A., … Ghedin, E. (n.d.).Publication year
2020Journal title
Nature communicationsVolume
11Issue
1AbstractSex determination mechanisms often differ even between related species yet the evolution of sex chromosomes remains poorly understood in all but a few model organisms. Some nematodes such as Caenorhabditis elegans have an XO sex determination system while others, such as the filarial parasite Brugia malayi, have an XY mechanism. We present a complete B. malayi genome assembly and define Nigon elements shared with C. elegans, which we then map to the genomes of other filarial species and more distantly related nematodes. We find a remarkable plasticity in sex chromosome evolution with several distinct cases of neo-X and neo-Y formation, X-added regions, and conversion of autosomes to sex chromosomes from which we propose a model of chromosome evolution across different nematode clades. The phylum Nematoda offers a new and innovative system for gaining a deeper understanding of sex chromosome evolution.Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection
AbstractBissel, S. J., Carter, C. E., Wang, G., Johnson, S. K., Lashua, L. P., Kelvin, A. A., Wiley, C. A., Ghedin, E., & Ross, T. M. (n.d.).Publication year
2019Journal title
American Journal of PathologyVolume
189Issue
12Page(s)
2389-2399AbstractInfluenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus–induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age.Development and characterization of a reverse-genetics system for influenza D virus
AbstractYu, J., Liu, R., Zhou, B., Chou, T. W., Ghedin, E., Sheng, Z., Gao, R., Zhai, S. L., Wang, D., & Lia, F. (n.d.).Publication year
2019Journal title
Journal of virologyVolume
93Issue
21AbstractInfluenza D virus (IDV) of the Orthomyxoviridae family has a wide host range and a broad geographical distribution. Recent IDV outbreaks in swine along with serological and genetic evidence of IDV infection in humans have raised concerns regarding the zoonotic potential of this virus. To better study IDV at the molecular level, a reverse-genetics system (RGS) is urgently needed, but to date, no RGS had been described for IDV. In this study, we rescued the recombinant influenza D/swine/Oklahoma/1314/2011 (D/OK) virus by using a bidirectional seven-plasmid-based system and further characterized rescued viruses in terms of growth kinetics, replication stability, and receptor-binding capacity. Our results collectively demonstrated that RGS-derived viruses resembled the parental viruses for these properties, thereby supporting the utility of this RGS to study IDV infection biology. In addition, we developed an IDV minigenome replication assay and identified the E697K mutation in PB1 and the L462F mutation in PB2 that directly affected the activity of the IDV ribonucleoprotein (RNP) complex, resulting in either attenuated or replication-incompetent viruses. Finally, by using the minigenome replication assay, we demonstrated that a single nucleotide polymorphism at position 5 of the 3= conserved noncoding region in IDV and influenza C virus (ICV) resulted in the inefficient cross-recognition of the heterotypic promoter by the viral RNP complex. In conclusion, we successfully developed a minigenome replication assay and a robust reverse-genetics system that can be used to further study replication, tropism, and pathogenesis of IDV. IMPORTANCE Influenza D virus (IDV) is a new type of influenza virus that uses cattle as the primary reservoir and infects multiple agricultural animals. Increased outbreaks in pigs and serological and genetic evidence of human infection have raised concerns about potential IDV adaptation in humans. Here, we have developed a plasmid-based IDV reverse-genetics system that can generate infectious viruses with replication kinetics similar to those of wild-type viruses following transfection of cultured cells. Further characterization demonstrated that viruses rescued from the described RGS resembled the parental viruses in biological and receptor-binding properties. We also developed and validated an IDV minireplicon reporter system that specifically measures viral RNA polymerase activity. In summary, the reverse-genetics system and minireplicon reporter assay described in this study should be of value in identifying viral determinants of cross-species transmission and pathogenicity of novel influenza D viruses.Global phylogeography and ancient evolution of the widespread human gut virus crAssphage
AbstractEdwards, R. A., Vega, A. A., Norman, H. M., Ohaeri, M., Levi, K., Dinsdale, E. A., Cinek, O., Aziz, R. K., McNair, K., Barr, J. J., Bibby, K., Brouns, S. J., Cazares, A., De Jonge, P. A., Desnues, C., Díaz Muñoz, S. L., Fineran, P. C., Kurilshikov, A., Lavigne, R., … Dutilh, B. E. (n.d.).Publication year
2019Journal title
Nature MicrobiologyVolume
4Issue
10Page(s)
1727-1736AbstractMicrobiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world’s countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.Microbial composition of the human nasopharynx varies according to influenza virus type and vaccination status
AbstractDing, T., Song, T., Zhou, B., Geber, A., Ma, Y., Zhang, L., Volk, M., Kapadia, S. N., Jenkins, S. G., Salvatore, M., & Ghedin, E. (n.d.).Publication year
2019Journal title
mBioVolume
10Issue
4AbstractFactors that contribute to enhanced susceptibility to severe bacterial disease after influenza virus infection are not well defined but likely include the microbiome of the respiratory tract. Vaccination against influenza, while having variable effectiveness, could also play a role in microbial community stability. We collected nasopharyngeal samples from 215 individuals infected with influenza A/H3N2 or influenza B virus and profiled the microbiota by target sequencing of the 16S rRNA gene. We identified signature taxonomic groups by performing linear discriminant analysis and effective size comparisons (LEfSe) and defined bacterial community types using Dirichlet multinomial mixture (DMM) models. Influenza infection was shown to be significantly associated with microbial composition of the nasopharynx according to the virus type and the vaccination status of the patient. We identified four microbial community types across the combined cohort of influenza patients and healthy individuals with one community type most representative of the influenza virus-infected group. We also identified microbial taxa for which relative abundance was significantly higher in the unvaccinated elderly group; these taxa include species known to be associated with pneumonia. IMPORTANCE Our results suggest that there is a significant association between the composition of the microbiota in the nasopharynx and the influenza virus type causing the infection. We observe that vaccination status, especially in more senior individuals, also has an association with the microbial community profile. This indicates that vaccination against influenza, even when ineffective to prevent disease, could play a role in controlling secondary bacterial complications.Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia
AbstractVoronin, D., Schnall, E., Grote, A., Jawahar, S., Ali, W., Unnasch, T. R., Ghedin, E., & Lustigman, S. (n.d.).Publication year
2019Journal title
PLoS PathogensVolume
15Issue
9AbstractHuman parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.Reply to ‘Reconciling disparate estimates of viral genetic diversity during human influenza infections’
Poon, L. L., Song, T., Wentworth, D. E., Holmes, E. C., Greenbaum, B. D., Peiris, J. S., Cowling, B. J., & Ghedin, E. (n.d.). In Nature Genetics (1–).Publication year
2019Volume
51Issue
9Page(s)
1301-1303Taxonomy of the order Mononegavirales: second update 2018
AbstractMaes, P., Amarasinghe, G. K., Ayllón, M. A., Basler, C. F., Bavari, S., Blasdell, K. R., Briese, T., Brown, P. A., Bukreyev, A., Balkema-Buschmann, A., Buchholz, U. J., Chandran, K., Crozier, I., De Swart, R. L., Dietzgen, R. G., Dolnik, O., Domier, L. L., Drexler, J. F., Dürrwald, R., … Kuhn, J. H. (n.d.).Publication year
2019Journal title
Archives of VirologyVolume
164Issue
4Page(s)
1233-1244AbstractIn October 2018, the order Mononegavirales was amended by the establishment of three new families and three new genera, abolishment of two genera, and creation of 28 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).