Professor of Epidemiology
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.
BS, Biology, McGill University, Montreal, CanadaMS, Environmental Sciences, University of Quebec, Montreal, CanadaPhD, Molecular Parasitology, McGill University, Montreal, Canada
American Academy of Microbiology Fellow (2017)Kavli Frontiers of Science Fellow (2012)MacArthur Fellow (2011)Chancellor’s Distinguished Research Award (2010)
BiologyGenomicsInfectious DiseasesViral Infections
Fungi stabilize connectivity in the lung and skin microbial ecosystemsTipton, L., Müller, C. L., Kurtz, Z. D., Huang, L., Kleerup, E., Morris, A., Bonneau, R., & Ghedin, E.
Issue1Background: No microbe exists in isolation, and few live in environments with only members of their own kingdom or domain. As microbiome studies become increasingly more interested in the interactions between microbes than in cataloging which microbes are present, the variety of microbes in the community should be considered. However, the majority of ecological interaction networks for microbiomes built to date have included only bacteria. Joint association inference across multiple domains of life, e.g., fungal communities (the mycobiome) and bacterial communities, has remained largely elusive. Results: Here, we present a novel extension of the SParse InversE Covariance estimation for Ecological ASsociation Inference (SPIEC-EASI) framework that allows statistical inference of cross-domain associations from targeted amplicon sequencing data. For human lung and skin micro- and mycobiomes, we show that cross-domain networks exhibit higher connectivity, increased network stability, and similar topological re-organization patterns compared to single-domain networks. We also validate in vitro a small number of cross-domain interactions predicted by the skin association network. Conclusions: For the human lung and skin micro- and mycobiomes, our findings suggest that fungi play a stabilizing role in ecological network organization. Our study suggests that computational efforts to infer association networks that include all forms of microbial life, paired with large-scale culture-based association validation experiments, will help formulate concrete hypotheses about the underlying biological mechanisms of species interactions and, ultimately, help understand microbial communities as a whole.
Measuring associations between the microbiota and repeated measures of continuous clinical variables using a lasso-penalized generalized linear mixed modelTipton, L., Cuenco, K. T., Huang, L., Greenblatt, R. M., Kleerup, E., Sciurba, F., Duncan, S. R., Donahoe, M. P., Morris, A., & Ghedin, E.
Journal titleBioData Mining
Issue1Background: Human microbiome studies in clinical settings generally focus on distinguishing the microbiota in health from that in disease at a specific point in time. However, microbiome samples may be associated with disease severity or continuous clinical health indicators that are often assessed at multiple time points. While the temporal data from clinical and microbiome samples may be informative, analysis of this type of data can be problematic for standard statistical methods. Results: To identify associations between microbiota and continuous clinical variables measured repeatedly in two studies of the respiratory tract, we adapted a statistical method, the lasso-penalized generalized linear mixed model (LassoGLMM). LassoGLMM can screen for associated clinical variables, incorporate repeated measures of individuals, and address the large number of species found in the microbiome. As is common in microbiome studies, when the number of variables is an order of magnitude larger than the number of samples LassoGLMM can be imperfect in its variable selection. We overcome this limitation by adding a pre-screening step to reduce the number of variables evaluated in the model. We assessed the use of this adapted two-stage LassoGLMM for its ability to determine which microbes are associated with continuous repeated clinical measures. We found associations (retaining a non-zero coefficient in the LassoGLMM) between 10 laboratory measurements and 43 bacterial genera in the oral microbiota, and between 2 cytokines and 3 bacterial genera in the lung. We compared our associations with those identified by the Wilcoxon test after dichotomizing our outcomes and identified a non-significant trend towards differential abundance between high and low outcomes. Our two-step LassoGLMM explained more of the variance seen in the outcome of interest than other variants of the LassoGLMM method. Conclusions: We demonstrated a method that can account for the large number of genera detected in microbiome studies and repeated measures of clinical or longitudinal studies, allowing for the detection of strong associations between microbes and clinical measures. By incorporating the design strengths of repeated measurements and a prescreening step to aid variable selection, our two-step LassoGLMM will be a useful analytic method for investigating relationships between microbes and repeatedly measured continuous outcomes.
Taxonomy of the order Mononegavirales: update 2018Amarasinghe, G. K., Aréchiga Ceballos, N. G., Banyard, A. C., Basler, C. F., Bavari, S., Bennett, A. J., Blasdell, K. R., Briese, T., Bukreyev, A., Caì, Y., Calisher, C. H., Campos Lawson, C., Chandran, K., Chapman, C. A., Chiu, C. Y., Choi, K. S., Collins, P. L., Dietzgen, R. G., Dolja, V. V., Dolnik, O., Domier, L. L., Dürrwald, R., Dye, J. M., Easton, A. J., Ebihara, H., Echevarría, J. E., Fooks, A. R., Formenty, P. B., Fouchier, R. A., Freuling, C. M., Ghedin, E., Goldberg, T. L., Hewson, R., Horie, M., Hyndman, T. H., Jiāng, D., Kityo, R., Kobinger, G. P., Kondō, H., Koonin, E. V., Krupovic, M., Kurath, G., Lamb, R. A., Lee, B., Leroy, E. M., Maes, P., Maisner, A., Marston, D. A., Mor, S. K., Müller, T., Mühlberger, E., Ramírez, V. M., Netesov, S. V., Ng, T. F., Nowotny, N., Palacios, G., Patterson, J. L., Pawęska, J. T., Payne, S. L., Prieto, K., Rima, B. K., Rota, P., Rubbenstroth, D., Schwemmle, M., Siddell, S., Smither, S. J., Song, Q., Song, T., Stenglein, M. D., Stone, D. M., Takada, A., Tesh, R. B., Thomazelli, L. M., Tomonaga, K., Tordo, N., Towner, J. S., Vasilakis, N., Vázquez-Morón, S., Verdugo, C., Volchkov, V. E., Wahl, V., Walker, P. J., Wang, D., Wang, L. F., Wellehan, J. F., Wiley, M. R., Whitfield, A. E., Wolf, Y. I., Yè, G., Zhāng, Y. Z., & Kuhn, J. H.
Journal titleArchives of Virology
Page(s)1-12In 2018, the order Mononegavirales was expanded by inclusion of 1 new genus and 12 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV) and summarizes additional taxonomic proposals that may affect the order in the near future.
Characterization of five unclassified orthobunyaviruses (Bunyaviridae) from Africa and the AmericasRogers, M. B., Gulino, K. M., Tesh, R. B., Cui, L., Fitch, A., Unnasch, T. R., Popov, V. L., Travassos da Rosa, A. P., Guzman, H., Carrera, J. P., Vasilakis, N., & Ghedin, E.
Journal titleJournal of General Virology
Page(s)2258-2266The Bunyaviridae family is made up of a diverse range of viruses, some of which cause disease and are a cause for concern in human and veterinary health. Here, we report the genomic and antigenic characterization of five previously uncharacterized bunyaviruses. Based on their ultrastructure, antigenic relationships and phylogenomic relationships, the five viruses are classified as members of the Orthobunyavirus genus. Three are viruses in the California encephalitis virus serogroup and are related to Trivittatus virus; the two others are most similar to the Mermet virus in the Simbu serogroup, and to the Tataguine virus, which is not currently assigned to a serogroup. Each of these five viruses was pathogenic to newborn mice, indicating their potential to cause illness in humans and other animals.
Defining Brugia malayi and Wolbachia symbiosis by stage-specific dual RNA-seqGrote, A., Voronin, D., Ding, T., Twaddle, A., Unnasch, T. R., Lustigman, S., & Ghedin, E.
Journal titlePLoS Neglected Tropical Diseases
Issue3Background: Filarial nematodes currently infect up to 54 million people worldwide, with millions more at risk for infection, representing the leading cause of disability in the developing world. Brugia malayi is one of the causative agents of lymphatic filariasis and remains the only human filarial parasite that can be maintained in small laboratory animals. Many filarial nematode species, including B. malayi, carry an obligate endosymbiont, the alpha-proteobacteria Wolbachia, which can be eliminated through antibiotic treatment. Elimination of the endosymbiont interferes with development, reproduction, and survival of the worms within the mamalian host, a clear indicator that the Wolbachia are crucial for survival of the parasite. Little is understood about the mechanism underlying this symbiosis. Methodology/ Principle findings: To better understand the molecular interplay between these two organisms we profiled the transcriptomes of B. malayi and Wolbachia by dual RNA-seq across the life cycle of the parasite. This helped identify functional pathways involved in this essential symbiotic relationship provided by the co-expression of nematode and bacterial genes. We have identified significant stage-specific and gender-specific differential expression in Wolbachia during the nematode’s development. For example, during female worm development we find that Wolbachia upregulate genes involved in ATP production and purine biosynthesis, as well as genes involved in the oxidative stress response. Conclusions/ Significance: This global transcriptional analysis has highlighted specific pathways to which both Wolbachia and B. malayi contribute concurrently over the life cycle of the parasite, paving the way for the development of novel intervention strategies.
Evolution and cryo-electron microscopy capsid structure of a north american bat adenovirus and its relationship to other mastadenovirusesHackenbrack, N., Rogers, M. B., Ashley, R. E., Keel, M. K., Kubiski, S. V., Bryan, J. A., Ghedin, E., Holmes, E. C., Hafenstein, S. L., & Allison, A. B.
Journal titleJournal of Virology
Issue2Since the first description of adenoviruses in bats in 2006, a number of micro- and megabat species in Europe, Africa, and Asia have been shown to carry a wide diversity of adenoviruses. Here, we report on the evolutionary, biological, and structural characterization of a novel bat adenovirus (BtAdV) recovered from a Rafinesque's big-eared bat (Corynorhinus rafinesquii) in Kentucky, USA, which is the first adenovirus isolated from North American bats. This virus (BtAdV 250-A) exhibits a close phylogenetic relationship with Canine mastadenovirus A (CAdV A), as previously observed with other BtAdVs. To further investigate the relationships between BtAdVs and CAdVs, we conducted mass spectrometric analysis and single-particle cryo-electron microscopy reconstructions of the BtAdV 250-A capsid and also analyzed the in vitro host ranges of both viruses. Our results demonstrate that BtAdV 250-A represents a new mastadenovirus species that, in contrast to CAdV, has a unique capsid morphology that contains more prominent extensions of protein IX and can replicate efficiently in a phylogenetically diverse range of species. These findings, in addition to the recognition that both the genetic diversity of BtAdVs and the number of different bat species from disparate geographic regions infected with BtAdVs appears to be extensive, tentatively suggest that bats may have served as a potential reservoir for the cross-species transfer of adenoviruses to other hosts, as theorized for CAdV.
Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in AustraliaKerr, P. J., Cattadori, I. M., Rogers, M. B., Fitch, A., Geber, A., Liu, J., Sim, D. G., Boag, B., Eden, J. S., Ghedin, E., Read, A. F., & Holmes, E. C.
Journal titlePLoS Pathogens
Issue3The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954–1955) and between 2008–2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms.
ICTV Virus Taxonomy Profile: NyamiviridaeDietzgen, R. G., Ghedin, E., Jiāng, D., Kuhn, J. H., Song, T., Vasilakis, N., Wang, D., & Ictv Report Consortium, R. C.
Journal titleThe Journal of general virology
Page(s)2914-2915The Nyamiviridae is a family of viruses with unsegmented, negative-sense RNA genomes of 11.3-12.2 kb that produce enveloped, spherical virions. Viruses of the genus Nyavirus are tick-borne and some also infect birds. Other nyamiviruses infecting parasitoid wasps and plant parasitic nematodes have been classified into the genera Peropuvirus and Socyvirus, respectively. This is a summary of the current International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Nyamiviridae, which is available at www.ictv.global/report/nyamiviridae.
Integrative gene network analysis identifies key signatures, intrinsic networks and host factors for influenza virus A infectionsForst, C. V., Zhou, B., Wang, M., Chou, T. W., Mason, G., Song, W. M., Schadt, E., Ghedin, E., & Zhang, B.
Journal titlenpj Systems Biology and Applications
Issue1Influenza A virus, with the limited coding capacity of 10–14 proteins, requires the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only reveals molecular pathways exploited by the virus or triggered by the immune system, but also provides further targets for antiviral drug development. To uncover novel pathways and key targets of influenza infection, we assembled a large amount of data from 12 cell-based gene-expression studies of influenza infection for an integrative network analysis. We systematically identified differentially expressed genes and gene co-expression networks induced by influenza infection. We revealed the dedicator of cytokinesis 5 (DOCK5) played potentially an important role for influenza virus replication. CRISPR/Cas9 knockout of DOCK5 reduced influenza virus replication, indicating that DOCK5 is a key regulator for the viral life cycle. DOCK5’s targets determined by the DOCK5 knockout experiments strongly validated the predicted gene signatures and networks. This study systematically uncovered and validated fundamental patterns of molecular responses, intrinsic structures of gene co-regulation, and novel key targets in influenza virus infection.
Lessons from the genomes and transcriptomes of filarial nematodesGrote, A., Lustigman, S., & Ghedin, E.
Journal titleMolecular and Biochemical ParasitologyHuman filarial infections are a leading cause of morbidity in the developing world. While a small arsenal of drugs exists to treat these infections, there remains a tremendous need for the development of additional interventions. Recent genome sequences and transcriptome analyses of filarial nematodes have provided novel biological insight and allowed for the prediction of novel drug targets as well as potential vaccine candidates. In this review, we discuss the currently available data, insights gained into the metabolism of these organisms, and how the filaria field can move forward by leveraging these data.
Multiplex reverse transcription-PCR for simultaneous surveillance of influenza A and B virusesZhou, B., Deng, Y. M., Barnes, J. R., Sessions, O. M., Chou, T. W., Wilson, M., Stark, T. J., Volk, M., Spirason, N., Halpin, R. A., Kamaraj, U. S., Ding, T., Stockwell, T. B., Salvatore, M., Ghedin, E., Barr, I. G., & Wentworth, D. E.
Journal titleJournal of Clinical Microbiology
Page(s)3492-3501Influenza A and B viruses are the causative agents of annual influenza epidemics that can be severe, and influenza A viruses intermittently cause pandemics. Sequence information from influenza virus genomes is instrumental in determining mechanisms underpinning antigenic evolution and antiviral resistance. However, due to sequence diversity and the dynamics of influenza virus evolution, rapid and high-throughput sequencing of influenza viruses remains a challenge. We developed a single-reaction influenza A/B virus (FluA/B) multiplex reverse transcription-PCR (RTPCR) method that amplifies the most critical genomic segments (hemagglutinin [HA], neuraminidase [NA], and matrix [M]) of seasonal influenza A and B viruses for next-generation sequencing, regardless of viral type, subtype, or lineage. Herein, we demonstrate that the strategy is highly sensitive and robust. The strategy was validated on thousands of seasonal influenza A and B virus-positive specimens using multiple next-generation sequencing platforms.
Possibility and challenges of conversion of current virus species names to Linnaean binomialsPostler, T. S., Clawson, A. N., Amarasinghe, G. K., Basler, C. F., Bavari, S., Benko, M., Blasdell, K. R., Briese, T., Buchmeier, M. J., Bukreyev, A., Calisher, C. H., Chandran, K., Charrel, R., Clegg, C. S., Collins, P. L., De La Torre, J. C., DeRisi, J. L., Dietzgen, R. G., Dolnik, O., Dürrwald, R., Dye, J. M., Easton, A. J., Emonet, S., Formenty, P., Fouchier, R. A., Ghedin, E., Gonzalez, J. P., Harrach, B., Hewson, R., Horie, M., Jiāng, D., Kobinger, G., Kondo, H., Kropinski, A. M., Krupovic, M., Kurath, G., Lamb, R. A., Leroy, E. M., Lukashevich, I. S., Maisner, A., Mushegian, A. R., Netesov, S. V., Nowotny, N., Patterson, J. L., Payne, S. L., Paweska, J. T., Peters, C. J., Radoshitzky, S. R., Rima, B. K., Romanowski, V., Rubbenstroth, D., Sabanadzovic, S., Sanfaçon, H., Salvato, M. S., Schwemmle, M., Smither, S. J., Stenglein, M. D., Stone, D. M., Takada, A., Tesh, R. B., Tomonaga, K., Tordo, N., Towner, J. S., Vasilakis, N., Volchkov, V. E., Wahl-Jensen, V., Walker, P. J., Wang, L. F., Varsani, A., Whitfield, A. E., Murilo Zerbini, F., & Kuhn, J. H.
Journal titleSystematic Biology
Page(s)463-473Botanical, mycological, zoological, and prokaryotic species names follow the Linnaean format, consisting of an italicized Latinized binomen with a capitalized genus name and a lower case species epithet (e.g., Homo sapiens). Virus species names, however, do not follow a uniform format, and, even when binomial, are not Linnaean in style. In this thought exercise, we attempted toconvert all currently official names ofspecies included in the virusfamily Arenaviridae and the virus order Mononegavirales to Linnaean binomials, and to identify and address associated challenges and concerns. Surprisingly, this endeavor was not as complicated or time-consuming as even the authors of this article expected when conceiving the experiment.
Taxonomy of the order Mononegavirales: update 2017Amarasinghe, G. K., Bào, Y., Basler, C. F., Bavari, S., Beer, M., Bejerman, N., Blasdell, K. R., Bochnowski, A., Briese, T., Bukreyev, A., Calisher, C. H., Chandran, K., Collins, P. L., Dietzgen, R. G., Dolnik, O., Dürrwald, R., Dye, J. M., Easton, A. J., Ebihara, H., Fang, Q., Formenty, P., Fouchier, R. A., Ghedin, E., Harding, R. M., Hewson, R., Higgins, C. M., Hong, J., Horie, M., James, A. P., Jiāng, D., Kobinger, G. P., Kondo, H., Kurath, G., Lamb, R. A., Lee, B., Leroy, E. M., Li, M., Maisner, A., Mühlberger, E., Netesov, S. V., Nowotny, N., Patterson, J. L., Payne, S. L., Paweska, J. T., Pearson, M. N., Randall, R. E., Revill, P. A., Rima, B. K., Rota, P., Rubbenstroth, D., Schwemmle, M., Smither, S. J., Song, Q., Stone, D. M., Takada, A., Terregino, C., Tesh, R. B., Tomonaga, K., Tordo, N., Towner, J. S., Vasilakis, N., Volchkov, V. E., Wahl-Jensen, V., Walker, P. J., Wang, B., Wang, D., Wang, F., Wang, L. F., Werren, J. H., Whitfield, A. E., Yan, Z., Ye, G., & Kuhn, J. H.
Journal titleArchives of Virology
Page(s)1-12In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Transmission bottleneck size estimation from pathogen deep-sequencing data, with an application to human influenza A virusLeonard, A. S., Weissman, D. B., Greenbaum, B., Ghedin, E., & Koelle, K.
Journal titleJournal of Virology
Issue14The bottleneck governing infectious disease transmission describes the size of the pathogen population transferred from the donor to the recipient host. Accurate quantification of the bottleneck size is particularly important for rapidly evolving pathogens such as influenza virus, as narrow bottlenecks reduce the amount of transferred viral genetic diversity and, thus, may decrease the rate of viral adaptation. Previous studies have estimated bottleneck sizes governing viral transmission by using statistical analyses of variants identified in pathogen sequencing data. These analyses, however, did not account for variant calling thresholds and stochastic viral replication dynamics within recipient hosts. Because these factors can skew bottleneck size estimates, we introduce a new method for inferring bottleneck sizes that accounts for these factors. Through the use of a simulated data set, we first show that our method, based on beta-binomial sampling, accurately recovers transmission bottleneck sizes, whereas other methods fail to do so. We then apply our method to a data set of influenza A virus (IAV) infections for which viral deepsequencing data from transmission pairs are available. We find that the IAV transmission bottleneck size estimates in this study are highly variable across transmission pairs, while the mean bottleneck size of 196 virions is consistent with a previous estimate for this data set. Furthermore, regression analysis shows a positive association between estimated bottleneck size and donor infection severity, as measured by temperature. These results support findings from experimental transmission studies showing that bottleneck sizes across transmission events can be variable and influenced in part by epidemiological factors.
Correlation of the lung microbiota with metabolic profiles in bronchoalveolar lavage fluid in HIV infectionCribbs, S. K., Uppal, K., Li, S., Jones, D. P., Huang, L., Tipton, L., Fitch, A., Greenblatt, R. M., Kingsley, L., Guidot, D. M., Ghedin, E., & Morris, A.
Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotypeSegal, L. N., Clemente, J. C., Tsay, J.- chieh J., Koralov, S. B., Keller, B. C., Wu, B. G., Li, Y., Shen, N., Ghedin, E., Morris, A., Diaz, P., Huang, L., Wikoff, W. R., Ubeda, C., Artacho, A., Rom, W. N., Sterman, D. H., Collman, R. G., Blaser, M. J., & Weiden, M. D.
Journal titleNature Reviews Microbiology
Glucose and glycogen metabolism in brugia malayi is associated with wolbachia symbiont fitnessVoronin, D., Bachu, S., Shlossman, M., Unnasch, T. R., Ghedin, E., & Lustigman, S.
Journal titlePLoS One
Issue4Wolbachia are endosymbiotic bacteria found in the majority of arthropods and filarial nematodes of medical and veterinary importance. They have evolved a wide range of symbiotic associations. In filarial nematodes that cause human lymphatic filariasis (Wuchereria bancrofti, Brugia malayi) or onchocerciasis (Onchocerca volvulus), Wolbachia are important for parasite development, reproduction and survival. The symbiotic bacteria rely in part on nutrients and energy sources provided by the host. Genomic analyses suggest that the strain of Wolbachia found in B. malayi (wBm) lacks the genes for two glycolytic enzymes-6-phosphofructokinase and pyruvate kinase-and is thus potentially unable to convert glucose into pyruvate, an important substrate for energy generation. The Wolbachia surface protein, wBm00432, is complexed to six B. malayi glycolytic enzymes, including aldolase. In this study we characterized two B. malayi aldolase isozymes and found that their expression is dependent on Wolbachia fitness and number. We confirmed by immuno-transmission electron microscopy that aldolase is associated with the Wolbachia surface. RNAi experiments suggested that aldolase-2 plays a significant role in both Wolbachia survival and embryogenesis in B. malayi. Treatment with doxycycline reduced Wolbachia fitness and increased the amount of both glucose and glycogen detected in the filarial parasite, indicating that glucose metabolism and glycogen storage in B. malayi are associated with Wolbachia fitness. This metabolic co-dependency between Wolbachia and its filarial nematode indicates that glycolysis could be a shared metabolic pathway between the bacteria and B. malayi, and thus a potential new target for anti-filarial therapy.
Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infectionMorris, A., Paulson, J. N., Talukder, H., Tipton, L., Kling, H., Cui, L., Fitch, A., Pop, M., Norris, K. A., & Ghedin, E.
Volume4Background: Longitudinal studies of the lung microbiome are challenging due to the invasive nature of sample collection. In addition, studies of the lung microbiome in human disease are usually performed after disease onset, limiting the ability to determine early events in the lung. We used a non-human primate model to assess lung microbiome alterations over time in response to an HIV-like immunosuppression and determined impact of the lung microbiome on development of obstructive lung disease. Cynomolgous macaques were infected with the SIV-HIV chimeric virus SHIV89.6P. Bronchoalveolar lavage fluid samples were collected pre-infection and every 4 weeks for 53 weeks post-infection. The microbiota was characterized at each time point by 16S ribosomal RNA (rRNA) sequencing. Results: We observed individual variation in the composition of the lung microbiota with a proportion of the macaques having Tropheryma whipplei as the dominant organism in their lungs. Bacterial communities varied over time both within and between animals, but there did not appear to be a systematic alteration due to SHIV infection. Development of obstructive lung disease in the SHIV-infected animals was characterized by a relative increase in abundance of oral anaerobes. Network analysis further identified a difference in community composition that accompanied the development of obstructive disease with negative correlations between members of the obstructed and non-obstructed groups. This emphasizes how species shifts can impact multiple other species, potentially resulting in disease. Conclusions: This study is the first to investigate the dynamics of the lung microbiota over time and in response to immunosuppression in a non-human primate model. The persistence of oral bacteria in the lung and their association with obstruction suggest a potential role in pathogenesis. The lung microbiome in the non-human primate is a valuable tool for examining the impact of the lung microbiome in human health and disease.
Quantifying influenza virus diversity and transmission in humansPoon, L. L., Song, T., Rosenfeld, R., Lin, X., Rogers, M. B., Zhou, B., Sebra, R., Halpin, R. A., Guan, Y., Twaddle, A., DePasse, J. V., Stockwell, T. B., Wentworth, D. E., Holmes, E. C., Greenbaum, B., Peiris, J. S., Cowling, B. J., & Ghedin, E.
Journal titleNature Genetics
Page(s)195-200Influenza A virus is characterized by high genetic diversity. However, most of what is known about influenza evolution has come from consensus sequences sampled at the epidemiological scale that only represent the dominant virus lineage within each infected host. Less is known about the extent of within-host virus diversity and what proportion of this diversity is transmitted between individuals. To characterize virus variants that achieve sustainable transmission in new hosts, we examined within-host virus genetic diversity in household donor-recipient pairs from the first wave of the 2009 H1N1 pandemic when seasonal H3N2 was co-circulating. Although the same variants were found in multiple members of the community, the relative frequencies of variants fluctuated, with patterns of genetic variation more similar within than between households. We estimated the effective population size of influenza A virus across donor-recipient pairs to be approximately 100-200 contributing members, which enabled the transmission of multiple lineages, including antigenic variants.
Stage-specific transcriptome and proteome analyses of the filarial parasite Onchocerca volvulus and its Wolbachia endosymbiontBennuru, S., Cotton, J. A., Ribeiro, J. M., Grote, A., Harsha, B., Holroyd, N., Mhashilkar, A., Molina, D. M., Randall, A. Z., Shandling, A. D., Unnasch, T. R., Ghedin, E., Berriman, M., Lustigman, S., & Nutman, T. B.
Issue6Onchocerciasis (river blindness) is a neglected tropical disease that has been successfully targeted by mass drug treatment programs in the Americas and small parts of Africa. Achieving the long-term goal of elimination of onchocerciasis, however, requires additional tools, including drugs, vaccines, and biomarkers of infection. Here, we describe the transcriptome and proteome profiles of the major vector and the human host stages (L1, L2, L3, molting L3, L4, adult male, and adult female) of Onchocerca volvulus along with the proteome of each parasitic stage and of its Wolbachia endosymbiont (wOv). In so doing, we have identified stage-specific pathways important to the parasite’s adaptation to its human host during its early development. Further, we generated a protein array that, when screened with well-characterized human samples, identified novel diagnostic biomarkers of O. volvulus infection and new potential vaccine candidates. This immunomic approach not only demonstrates the power of this postgenomic discovery platform but also provides additional tools for onchocerciasis control programs. IMPORTANCE The global onchocerciasis (river blindness) elimination program will have to rely on the development of new tools (drugs, vaccines, biomarkers) to achieve its goals by 2025. As an adjunct to the completed genomic sequencing of O. volvulus, we used a comprehensive proteomic and transcriptomic profiling strategy to gain a comprehensive understanding of both the vector-derived and human host-derived parasite stages. In so doing, we have identified proteins and pathways that enable novel drug targeting studies and the discovery of novel vaccine candidates, as well as useful biomarkers of active infection.
Taxonomy of the order Mononegavirales: update 2016Afonso, C. L., Amarasinghe, G. K., Bányai, K., Bào, Y., Basler, C. F., Bavari, S., Bejerman, N., Blasdell, K. R., Briand, F. X., Briese, T., Bukreyev, A., Calisher, C. H., Chandran, K., Chéng, J., Clawson, A. N., Collins, P. L., Dietzgen, R. G., Dolnik, O., Domier, L. L., Dürrwald, R., Dye, J. M., Easton, A. J., Ebihara, H., Farkas, S. L., Freitas-Astúa, J., Formenty, P., Fouchier, R. A., Fù, Y., Ghedin, E., Goodin, M. M., Hewson, R., Horie, M., Hyndman, T. H., Jiāng, D., Kitajima, E. W., Kobinger, G. P., Kondo, H., Kurath, G., Lamb, R. A., Lenardon, S., Leroy, E. M., Li, C. X., Lin, X. D., Liú, L., Longdon, B., Marton, S., Maisner, A., Mühlberger, E., Netesov, S. V., Nowotny, N., Patterson, J. L., Payne, S. L., Paweska, J. T., Randall, R. E., Rima, B. K., Rota, P., Rubbenstroth, D., Schwemmle, M., Shi, M., Smither, S. J., Stenglein, M. D., Stone, D. M., Takada, A., Terregino, C., Tesh, R. B., Tian, J. H., Tomonaga, K., Tordo, N., Towner, J. S., Vasilakis, N., Verbeek, M., Volchkov, V. E., Wahl-Jensen, V., Walsh, J. A., Walker, P. J., Wang, D., Wang, L. F., Wetzel, T., Whitfield, A. E., Xiè, J., Yuen, K. Y., Zhang, Y. Z., & Kuhn, J. H.
Journal titleArchives of Virology
Page(s)2351-2360In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
The genome of Onchocerca volvulus, agent of river blindnessCotton, J. A., Bennuru, S., Grote, A., Harsha, B., Tracey, A., Beech, R., Doyle, S. R., Dunn, M., Hotopp, J. C., Holroyd, N., Kikuchi, T., Lambert, O., Mhashilkar, A., Mutowo, P., Nursimulu, N., Ribeiro, J. M., Rogers, M. B., Stanley, E., Swapna, L. S., Tsai, I. J., Unnasch, T. R., Voronin, D., Parkinson, J., Nutman, T. B., Ghedin, E., Berriman, M., & Lustigman, S.
Journal titleNature Microbiology
Volume2Human onchocerciasis is a serious neglected tropical disease caused by the filarial nematode Onchocerca volvulus that can lead to blindness and chronic disability. Control of the disease relies largely on mass administration of a single drug, and the development of new drugs and vaccines depends on a better knowledge of parasite biology. Here, we describe the chromosomes of O. volvulus and its Wolbachia endosymbiont. We provide the highest-quality sequence assembly for any parasitic nematode to date, giving a glimpse into the evolution of filarial parasite chromosomes and proteomes. This resource was used to investigate gene families with key functions that could be potentially exploited as targets for future drugs. Using metabolic reconstruction of the nematode and its endosymbiont, we identified enzymes that are likely to be essential for O. volvulus viability. In addition, we have generated a list of proteins that could be targeted by Federal-Drug-Agency-approved but repurposed drugs, providing starting points for anti-onchocerciasis drug development.
The metagenomics and metadesign of the subways and Urban biomes (MetaSUB) international consortium inaugural meeting reportFailed generating bibliography.Abstract
Volume4The Metagenomics and Metadesign of the Subways and Urban Biomes (MetaSUB) International Consortium is a novel, interdisciplinary initiative comprised of experts across many fields, including genomics, data analysis, engineering, public health, and architecture. The ultimate goal of the MetaSUB Consortium is to improve city utilization and planning through the detection, measurement, and design of metagenomics within urban environments. Although continual measures occur for temperature, air pressure, weather, and human activity, including longitudinal, cross-kingdom ecosystem dynamics can alter and improve the design of cities. The MetaSUB Consortium is aiding these efforts by developing and testing metagenomic methods and standards, including optimized methods for sample collection, DNA/RNA isolation, taxa characterization, and data visualization. The data produced by the consortium can aid city planners, public health officials, and architectural designers. In addition, the study will continue to lead to the discovery of new species, global maps of antimicrobial resistance (AMR) markers, and novel biosynthetic gene clusters (BGCs). Finally, we note that engineered metagenomic ecosystems can help enable more responsive, safer, and quantified cities.
Cyclic avian mass mortality in the northeastern United States is associated with a novel orthomyxovirusAllison, A. B., Ballard, J. R., Tesh, R. B., Brown, J. D., Ruder, M. G., Keel, M. K., Munk, B. A., Mickley, R. M., Gibbs, S. E., Travassos da Rosa, A. P., Ellis, J. C., Ip, H. S., Shearn-Bochsler, V. I., Rogers, M. B., Ghedin, E., Holmes, E. C., Parrish, C. R., & Dwyer, C.
Journal titleJournal of Virology
Page(s)1389-1403Since 1998, cyclic mortality events in common eiders (Somateria mollissima), numbering in the hundreds to thousands of dead birds, have been documented along the coast of Cape Cod, MA, USA. Although longitudinal disease investigations have uncovered potential contributing factors responsible for these outbreaks, detecting a primary etiological agent has proven enigmatic. Here, we identify a novel orthomyxovirus, tentatively named Wellfleet Bay virus (WFBV), as a potential causative agent of these outbreaks. Genomic analysis of WFBV revealed that it is most closely related to members of the Quaranjavirus genus within the family Orthomyxoviridae. Similar to other members of the genus, WFBV contains an alphabaculovirus gp64-like glycoprotein that was demonstrated to have fusion activity; this also tentatively suggests that ticks (and/or insects) may vector the virus in nature. However, in addition to the six RNA segments encoding the prototypical structural proteins identified in other quaranjaviruses, a previously unknown RNA segment (segment 7) encoding a novel protein designated VP7 was discovered in WFBV. Although WFBV shows low to moderate levels of sequence similarity to Quaranfil virus and Johnston Atoll virus, the original members of the Quaranjavirus genus, additional antigenic and genetic analyses demonstrated that it is closely related to the recently identified Cygnet River virus (CyRV) from South Australia, suggesting that WFBV and CyRV may be geographic variants of the same virus. Although the identification of WFBV in part may resolve the enigma of these mass mortality events, the details of the ecology and epidemiology of the virus remain to be determined.
Development of high-yield influenza A virus vaccine virusesPing, J., Lopes, T. J., Nidom, C. A., Ghedin, E., MacKen, C. A., Fitch, A., Imai, M., Maher, E. A., Neumann, G., & Kawaoka, Y.
Journal titleNature Communications
Volume6Vaccination is one of the most cost-effective ways to prevent infection. Influenza vaccines propagated in cultured cells are approved for use in humans, but their yields are often suboptimal. Here, we screened A/Puerto Rico/8/34 (PR8) virus mutant libraries to develop vaccine backbones (defined here as the six viral RNA segments not encoding haemagglutinin and neuraminidase) that support high yield in cell culture. We also tested mutations in the coding and regulatory regions of the virus, and chimeric haemagglutinin and neuraminidase genes. A combination of high-yield mutations from these screens led to a PR8 backbone that improved the titres of H1N1, H3N2, H5N1 and H7N9 vaccine viruses in African green monkey kidney and Madin-Darby canine kidney cells. This PR8 backbone also improves titres in embryonated chicken eggs, a common propagation system for influenza viruses. This PR8 vaccine backbone thus represents an advance in seasonal and pandemic influenza vaccine development.