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
Comparative analysis of the complete genome sequence of the california msw strain of myxoma virus reveals potential host adaptations
AbstractKerr, P. J., Rogers, M. B., Fitch, A., DePasse, J. V., Cattadori, I. M., Hudson, P. J., Tscharke, D. C., Holmes, E. C., & Ghedin, E. (n.d.).Publication year
2013Journal title
Journal of virologyVolume
87Issue
22Page(s)
12080-12089AbstractMyxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right-hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits.Comparison of the respiratory microbiome in healthy nonsmokers and smokers
AbstractMorris, A., Beck, J. M., Schloss, P. D., Campbell, T. B., Crothers, K., Curtis, J. L., Flores, S. C., Fontenot, A. P., Ghedin, E., Huang, L., Jablonski, K., Kleerup, E., Lynch, S. V., Sodergren, E., Twigg, H., Young, V. B., Bassis, C. M., Venkataraman, A., Schmidt, T. M., & Weinstock, G. M. (n.d.).Publication year
2013Journal title
American Journal of Respiratory and Critical Care MedicineVolume
187Issue
10Page(s)
1067-1075AbstractRationale: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome. Objectives: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort. Methods: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome. Measurements and Main Results: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutralmodel. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not. Conclusions: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specificbacteria appear insignificantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.Genome scale evolution of myxoma virus reveals host-pathogen adaptation and rapid geographic spread
AbstractKerr, P. J., Rogers, M. B., Fitch, A., DePasse, J. V., Cattadori, I. M., Twaddle, A. C., Hudson, P. J., Tscharke, D. C., Read, A. F., Holmes, E. C., & Ghedin, E. (n.d.).Publication year
2013Journal title
Journal of virologyVolume
87Issue
23Page(s)
12900-12915AbstractThe evolutionary interplay between myxoma virus (MYXV) and the European rabbit (Oryctolagus cuniculus) following release of the virus in Australia in 1950 as a biological control is a classic example of host-pathogen coevolution. We present a detailed genomic and phylogeographic analysis of 30 strains of MYXV, including the Australian progenitor strain Standard Laboratory Strain (SLS), 24 Australian viruses isolated from 1951 to 1999, and three isolates from the early radiation in Britain from 1954 and 1955. We show that in Australia MYXV has spread rapidly on a spatial scale, with multiple lineages cocirculating within individual localities, and that both highly virulent and attenuated viruses were still present in the field through the 1990s. In addition, the detection of closely related virus lineages at sites 1,000 km apart suggests that MYXV moves freely in geographic space, with mosquitoes, fleas, and rabbit migration all providing means of transport. Strikingly, despite multiple introductions, all modern viruses appear to be ultimately derived from the original introductions of SLS. The rapidity of MYXV evolution was also apparent at the genomic scale, with gene duplications documented in a number of viruses. Duplication of potential virulence genes may be important in increasing the expression of virulence proteins and provides the basis for the evolution of novel functions. Mutations leading to loss of open reading frames were surprisingly frequent and in some cases may explain attenuation, but no common mutations that correlated with virulence or attenuation were identified.Kolente virus, a rhabdovirus species isolated from ticks and bats in the Republic of Guinea
AbstractGhedin, E., Rogers, M. B., Widen, S. G., Guzman, H., Da Rosa, A. P. A. T., Wood, T. G., Fitch, A., Popov, V., Holmes, E. C., Walker, P. J., Vasilakis, N., & Tesh, R. B. (n.d.).Publication year
2013Journal title
Journal of General VirologyVolume
94Page(s)
2609-2615AbstractKolente virus (KOLEV) is a rhabdovirus originally isolated from ticks and a bat in Guinea, West Africa, in 1985. Although tests at the time of isolation suggested that KOLEV is a novel rhabdovirus, it has remained largely uncharacterized. We assembled the complete genome sequence of the prototype strain DakAr K7292, which was found to encode the five canonical rhabdovirus structural proteins (N, P, M, G and L) with alternative ORFs (.180 nt) in the P and L genes. Serologically, KOLEV exhibited a weak antigenic relationship with Barur and Fukuoka viruses in the Kern Canyon group. Phylogenetic analysis revealed that KOLEV represents a distinct and divergent lineage that shows no clear relationship to any rhabdovirus except Oita virus, although with limited phylogenetic resolution. In summary, KOLEV represents a novel species in the family Rhabdoviridae.Mammalian adaptation in the PB2 gene of avian H5N1 influenza virus
AbstractMin, J. Y., Santos, C., Fitch, A., Twaddle, A., Toyoda, Y., DePasse, J. V., Ghedin, E., & Subbarao, K. (n.d.).Publication year
2013Journal title
Journal of virologyVolume
87Issue
19Page(s)
10884-10888AbstractThe substitution of glutamic acid (E) for lysine (K) at position 627 of the PB2 protein of avian H5N1 viruses has been identified as a virulence and host range determinant for infection of mammals. Here, we report that the E-to-K host-adaptive mutation in the PB2 gene appeared from day 4 and 5 along the respiratory tracts of mice and was complete by day 6 postinoculation. This mutation correlated with efficient replication of the virus in mice.Niakha virus: A novel member of the family Rhabdoviridae isolated from phlebotomine sandflies in Senegal
AbstractVasilakis, N., Widen, S., Mayer, S. V., Seymour, R., Wood, T. G., Popov, V., Guzman, H., Travassos Da Rosa, A. P. A., Ghedin, E., Holmes, E. C., Walker, P. J., & Tesh, R. B. (n.d.).Publication year
2013Journal title
VirologyVolume
444Issue
1Page(s)
80-89AbstractMembers of the family Rhabdoviridae have been assigned to eight genera but many remain unassigned. Rhabdoviruses have a remarkably diverse host range that includes terrestrial and marine animals, invertebrates and plants. Transmission of some rhabdoviruses often requires an arthropod vector, such as mosquitoes, midges, sandflies, ticks, aphids and leafhoppers, in which they replicate. Herein we characterize Niakha virus (NIAV), a previously uncharacterized rhabdovirus isolated from phebotomine sandflies in Senegal. Analysis of the 11,124. nt genome sequence indicates that it encodes the five common rhabdovirus proteins with alternative ORFs in the M, G and L genes. Phylogenetic analysis of the L protein indicate that NIAV's closest relative is Oak Vale rhabdovirus, although in this analysis NIAV is still so phylogenetically distinct that it might be classified as distinct from the eight currently recognized Rhabdoviridae genera. This observation highlights the vast, and yet not fully recognized diversity, of this family.Sequence analysis of in vivo defective interfering-like RNA of influenza a H1N1 pandemic virus
AbstractSaira, K., Lin, X., DePasse, J. V., Halpin, R., Twaddle, A., Stockwell, T., Angus, B., Cozzi-Lepri, A., Delfino, M., Dugan, V., Dwyer, D. E., Freiberg, M., Horban, A., Losso, M., Lynfield, R., Wentworth, D. N., Holmes, E. C., Davey, R., Wentworth, D. E., & Ghedin, E. (n.d.).Publication year
2013Journal title
Journal of virologyVolume
87Issue
14Page(s)
8064-8074AbstractInfluenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.The human mycobiome in health and disease
AbstractCui, L., Morris, A., & Ghedin, E. (n.d.).Publication year
2013Journal title
Genome MedicineVolume
5Issue
7AbstractThe mycobiome, referring primarily to the fungal biota in an environment, is an important component of the human microbiome. Despite its importance, it has remained understudied. New culture-independent approaches to determine microbial diversity, such as next-generation sequencing methods, are greatly broadening our view of fungal importance. An integrative analysis of current studies shows that different body sites harbor specific fungal populations, and that diverse mycobiome patterns are associated with various diseases. By interfacing with other biomes, as well as with the host, the mycobiome probably contributes to the progression of fungus-associated diseases and plays an important role in health and disease.Use of bronchoalveolar lavage to assess the respiratory microbiome: Signal in the noise
Twigg, H. L., Morris, A., Ghedin, E., Curtis, J. L., Huffnagle, G. B., Crothers, K., Campbell, T. B., Flores, S. C., Fontenot, A. P., Beck, J. M., Huang, L., Lynch, S., Knox, K. S., & Weinstock, G. (n.d.). In The Lancet Respiratory Medicine (1–).Publication year
2013Volume
1Issue
5Page(s)
354-356Widespread colonization of the lung by Tropheryma whipplei in HIV infection
AbstractLozupone, C., Cota-Gomez, A., Palmer, B. E., Linderman, D. J., Charlson, E. S., Sodergren, E., Mitreva, M., Abubucker, S., Martin, J., Yao, G., Campbell, T. B., Flores, S. C., Ackerman, G., Stombaugh, J., Ursell, L., Beck, J. M., Curtis, J. L., Young, V. B., Lynchv, S. V., … Fontenot, A. P. (n.d.).Publication year
2013Journal title
American Journal of Respiratory and Critical Care MedicineVolume
187Issue
10Page(s)
1110-1117AbstractRationale: Lung infections caused by opportunistic or virulent pathogensare a principal cause of morbidityandmortality in HIVinfection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in individuals infected with HIV. Objectives: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. Methods:We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage (BAL) and mouths of 82 HIV-positive and 77 HIV-negative subjects. Measurements and Main Results: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple's disease, were significantly more frequent in BAL of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects, but only 1 HIV-negative individual (13.4 versus 1.3%; P = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on eight BAL samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lungderived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple's disease. Conclusions: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.Evolutionary History and Attenuation of Myxoma Virus on Two Continents
AbstractKerr, P. J., Ghedin, E., DePasse, J. V., Fitch, A., Cattadori, I. M., Hudson, P. J., Tscharke, D. C., Read, A. F., & Holmes, E. C. (n.d.).Publication year
2012Journal title
PLoS PathogensVolume
8Issue
10AbstractThe attenuation of myxoma virus (MYXV) following its introduction as a biological control into the European rabbit populations of Australia and Europe is the canonical study of the evolution of virulence. However, the evolutionary genetics of this profound change in host-pathogen relationship is unknown. We describe the genome-scale evolution of MYXV covering a range of virulence grades sampled over 49 years from the parallel Australian and European epidemics, including the high-virulence progenitor strains released in the early 1950s. MYXV evolved rapidly over the sampling period, exhibiting one of the highest nucleotide substitution rates ever reported for a double-stranded DNA virus, and indicative of a relatively high mutation rate and/or a continually changing selective environment. Our comparative sequence data reveal that changes in virulence involved multiple genes, likely losses of gene function due to insertion-deletion events, and no mutations common to specific virulence grades. Hence, despite the similarity in selection pressures there are multiple genetic routes to attain either highly virulent or attenuated phenotypes in MYXV, resulting in convergence for phenotype but not genotype.Filarial and Wolbachia genomics
AbstractScott, A. L., Ghedin, E., Nutman, T. B., McReynolds, L. A., Poole, C. B., Slatko, B. E., & Foster, J. M. (n.d.).Publication year
2012Journal title
Parasite ImmunologyVolume
34Issue
2Page(s)
121-129AbstractFilarial nematode parasites, the causative agents for a spectrum of acute and chronic diseases including lymphatic filariasis and river blindness, threaten the well-being and livelihood of hundreds of millions of people in the developing regions of the world. The 2007 publication on a draft assembly of the 95-Mb genome of the human filarial parasite Brugia malayi- representing the first helminth parasite genome to be sequenced - has been followed in rapid succession by projects that have resulted in the genome sequencing of six additional filarial species, seven nonfilarial nematode parasites of animals and nearly 30 plant parasitic and free-living species. Parallel to the genomic sequencing, transcriptomic and proteomic projects have facilitated genome annotation, expanded our understanding of stage-associated gene expression and provided a first look at the role of epigenetic regulation of filarial genomes through microRNAs. The expansion in filarial genomics will also provide a significant enrichment in our knowledge of the diversity and variability in the genomes of the endosymbiotic bacterium Wolbachia leading to a better understanding of the genetic principles that govern filarial-Wolbachia mutualism. The goal here is to provide an overview of the trends and advances in filarial and Wolbachia genomics.Large-scale sequencing and the natural history of model human RNA viruses
AbstractDugan, V. G., Saira, K., & Ghedin, E. (n.d.).Publication year
2012Journal title
Future VirologyVolume
7Issue
6Page(s)
563-573AbstractRNA virus exploration within the field of medical virology has greatly benefited from technological developments in genomics, deepening our understanding of viral dynamics and emergence. Large-scale first-generation technology sequencing projects have expedited molecular epidemiology studies at an unprecedented scale for two pathogenic RNA viruses chosen as models: influenza A virus and dengue. Next-generation sequencing approaches are now leading to a more in-depth analysis of virus genetic diversity, which is greater for RNA than DNA viruses because of high replication rates and the absence of proofreading activity of the RNA-dependent RNA polymerase. In the field of virus discovery, technological advancements and metagenomic approaches are expanding the catalogs of novel viruses by facilitating our probing into the RNA virus world.Migratory flyway and geographical distance are barriers to the gene flow of influenza virus among North American birds
AbstractLam, T. T. Y., Ip, H. S., Ghedin, E., Wentworth, D. E., Halpin, R. A., Stockwell, T. B., Spiro, D. J., Dusek, R. J., Bortner, J. B., Hoskins, J., Bales, B. D., Yparraguirre, D. R., & Holmes, E. C. (n.d.).Publication year
2012Journal title
Ecology LettersVolume
15Issue
1Page(s)
24-33AbstractDespite the importance of migratory birds in the ecology and evolution of avian influenza virus (AIV), there is a lack of information on the patterns of AIV spread at the intra-continental scale. We applied a variety of statistical phylogeographic techniques to a plethora of viral genome sequence data to determine the strength, pattern and determinants of gene flow in AIV sampled from wild birds in North America. These analyses revealed a clear isolation-by-distance of AIV among sampling localities. In addition, we show that phylogeographic models incorporating information on the avian flyway of sampling proved a better fit to the observed sequence data than those specifying homogeneous or random rates of gene flow among localities. In sum, these data strongly suggest that the intra-continental spread of AIV by migratory birds is subject to major ecological barriers, including spatial distance and avian flyway.Presence of oseltamivir-resistant pandemic A/H1N1 minor variants before drug therapy with subsequent selection and transmission
AbstractGhedin, E., Holmes, E. C., Depasse, J. V., Pinilla, L. T., Fitch, A., Hamelin, M. E., Papenburg, J., & Boivin, G. (n.d.).Publication year
2012Journal title
Journal of Infectious DiseasesVolume
206Issue
10Page(s)
1504-1511AbstractA small proportion (1-1.5) of 2009 pandemic influenza A/H1N1 virus strains (A[H1N1]pdm09) are oseltamivir resistant, almost exclusively because of a H275Y mutation in the neuraminidase protein. However, many individuals infected with resistant strains had not received antivirals. Whether drug-resistant viruses are initially present as minor variants in untreated individuals before they emerge as the dominant strain in a virus population is of great importance for predicting the speed at which resistance will arise. To address this issue, we used ultra-deep sequencing of viral populations from serial nasopharyngeal specimens from an immunocompromised child and from 2 individuals in a household outbreak. We observed that the Y275 mutation was present as a minor variant in infected hosts before the onset of therapy. We also found evidence for the transmission of this drug-resistant variant with drug-susceptible viruses. These observations provide important information on the relative fitness of the Y275 mutation in the absence of oseltamivir treatment.A deep sequencing approach to comparatively analyze the transcriptome of lifecycle stages of the filarial worm, brugia malayi
AbstractChoi, Y. J., Ghedin, E., Berriman, M., McQuillan, J., Holroyd, N., Mayhew, G. F., Christensen, B. M., & Michalski, M. L. (n.d.).Publication year
2011Journal title
PLoS neglected tropical diseasesVolume
5Issue
12AbstractBackground: Developing intervention strategies for the control of parasitic nematodes continues to be a significant challenge. Genomic and post-genomic approaches play an increasingly important role for providing fundamental molecular information about these parasites, thus enhancing basic as well as translational research. Here we report a comprehensive genome-wide survey of the developmental transcriptome of the human filarial parasite Brugia malayi. Methodology/Principal Findings: Using deep sequencing, we profiled the transcriptome of eggs and embryos, immature (≤3 days of age) and mature microfilariae (MF), third- and fourth-stage larvae (L3 and L4), and adult male and female worms. Comparative analysis across these stages provided a detailed overview of the molecular repertoires that define and differentiate distinct lifecycle stages of the parasite. Genome-wide assessment of the overall transcriptional variability indicated that the cuticle collagen family and those implicated in molting exhibit noticeably dynamic stage-dependent patterns. Of particular interest was the identification of genes displaying sex-biased or germline-enriched profiles due to their potential involvement in reproductive processes. The study also revealed discrete transcriptional changes during larval development, namely those accompanying the maturation of MF and the L3 to L4 transition that are vital in establishing successful infection in mosquito vectors and vertebrate hosts, respectively. Conclusions/Significance: Characterization of the transcriptional program of the parasite's lifecycle is an important step toward understanding the developmental processes required for the infectious cycle. We find that the transcriptional program has a number of stage-specific pathways activated during worm development. In addition to advancing our understanding of transcriptome dynamics, these data will aid in the study of genome structure and organization by facilitating the identification of novel transcribed elements and splice variants.Analysis of transcriptional regulation of tetracycline responsive genes in Brugia malayi
AbstractLiu, C., Kelen, P. V., Ghedin, E., Lustigman, S., & Unnasch, T. R. (n.d.).Publication year
2011Journal title
Molecular and Biochemical ParasitologyVolume
180Issue
2Page(s)
106-111AbstractThe Wolbachia endosymbiont of the human filarial parasites is necessary for parasite reproduction, making it an attractive chemotherapeutic target. Previous studies have demonstrated that mRNA levels of several nuclearly encoded genes are altered as a result of exposure to antibiotics that eliminate the endosymbiont, suggesting that they may be involved in maintaining the parasite-endosymbiont relationship. Here, we tested the hypothesis that the increase in mRNA levels of certain nuclearly encoded genes of Brugia malayi in response to tetracycline treatment involved specific regulatory elements present in the promoters of these genes. The promoters of three such genes (BmRPL13, BmRPS4 and BmHSP70) were tested for tetracycline responsiveness utilizing a homologous transient transcription system. Reporter gene expression driven by all three promoters was up-regulated in transfected embryos exposed to tetracycline. Substitution mutagenesis was employed to map the cis-acting elements responsible for this response in the BmHSP70 promoter. Tetracycline responsiveness was found to be distinct from the cis-acting elements involved in regulating the stress response from the BmHSP70 promoter; rather, tetracycline responsiveness was mediated by a TATAA-box like element. This study represents the first demonstration of small molecule-mediated gene regulation of a native B. malayi promoter.Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance
AbstractGhedin, E., Laplante, J., DePasse, J., Wentworth, D. E., Santos, R. P., Lepow, M. L., Porter, J., Stellrecht, K., Lin, X., Operario, D., Griesemer, S., Fitch, A., Halpin, R. A., Stockwell, T. B., Spiro, D. J., Holmes, E. C., & St George, K. (n.d.).Publication year
2011Journal title
Journal of Infectious DiseasesVolume
203Issue
2Page(s)
168-174AbstractMixed infections with seasonal influenza A virus strains are a common occurrence and an important source of genetic diversity. Prolonged viral shedding, as observed in immunocompromised individuals, can lead to mutational accumulation over extended periods. Recently, drug resistance was reported in immunosuppressed patients infected with the 2009 pandemic influenza A (H1N1) virus within a few days after oseltamivir treatment was initiated. To better understand the evolution and emergence of drug resistance in these circumstances, we used a deep sequencing approach to survey the viral population from an immunosuppressed patient infected with H1N1/2009 influenza and treated with neuraminidase inhibitors. This patient harbored 3 genetic variants from 2 phylogenetically distinct viral clades of pandemic H1N1/2009, strongly suggestive of mixed infection. Strikingly, one of these variants also developed drug resistance de novo in response to oseltamivir treatment. Immunocompromised individuals may, therefore, constitute an important source of genetic and phenotypic diversity, both through mixed infection and de novo mutation.Extensive geographical mixing of 2009 human H1N1 influenza a virus in a single university community
AbstractHolmes, E. C., Ghedin, E., Halpin, R. A., Stockwell, T. B., Zhang, X. Q., Fleming, R., Davey, R., Benson, C. A., Mehta, S., Taplitz, R., Liu, Y. T., Brouwer, K. C., Wentworth, D. E., Lin, X., & Schooley, R. T. (n.d.).Publication year
2011Journal title
Journal of virologyVolume
85Issue
14Page(s)
6923-6929AbstractDespite growing interest in the molecular epidemiology of influenza virus, the pattern of viral spread within individual communities remains poorly understood. To determine the phylogeography of influenza virus in a single population, we examined the spatial diffusion of H1N1/09 influenza A virus within the student body of the University of California, San Diego (UCSD), sampling for a 1-month period between October and November 2009. Despite the highly focused nature of our study, an analysis of complete viral genome sequences revealed between 24 and 33 independent introductions of H1N1/09 into the UCSD community, comprising much of the global genetic diversity in this virus. These data were also characterized by a relatively low level of on-campus transmission as well as extensive spatial mixing, such that there was little geographical clustering by either student residence or city ZIP code. Most notably, students experiencing illness on the same day and residing in the same dorm possessed phylogenetically distinct lineages. H1N1/09 influenza A virus is therefore characterized by a remarkable spatial fluidity, which is likely to impede community-based methods for its control, including class cancellations, quarantine, and chemoprophylaxis.Genomic and protein structural maps of adaptive evolution of human influenza a virus to increased virulence in the mouse
AbstractPing, J., Keleta, L., Forbes, N. E., Dankar, S., Stecho, W., Tyler, S., Zhou, Y., Babiuk, L., Weingartl, H., Halpin, R. A., Boyne, A., Bera, J., Hostetler, J., Fedorova, N. B., Proudfoot, K., Katzel, D. A., Stockwell, T. B., Ghedin, E., Spiro, D. J., & Brown, E. G. (n.d.).Publication year
2011Journal title
PloS oneVolume
6Issue
6AbstractAdaptive evolution is characterized by positive and parallel, or repeated selection of mutations. Mouse adaptation of influenza A virus (IAV) produces virulent mutants that demonstrate positive and parallel evolution of mutations in the hemagglutinin (HA) receptor and non-structural protein 1 (NS1) interferon antagonist genes. We now present a genomic analysis of all 11 genes of 39 mouse adapted IAV variants from 10 replicate adaptation experiments. Mutations were mapped on the primary and structural maps of each protein and specific mutations were validated with respect to virulence, replication, and RNA polymerase activity. Mouse adapted (MA) variants obtained after 12 or 20-21 serial infections acquired on average 5.8 and 7.9 nonsynonymous mutations per genome of 11 genes, respectively. Among a total of 115 nonsynonymous mutations, 51 demonstrated properties of natural selection including 27 parallel mutations. The greatest degree of parallel evolution occurred in the HA receptor and ribonucleocapsid components, polymerase subunits (PB1, PB2, PA) and NP. Mutations occurred in host nuclear trafficking factor binding sites as well as sites of virus-virus protein subunit interaction for NP, NS1, HA and NA proteins. Adaptive regions included cap binding and endonuclease domains in the PB2 and PA polymerase subunits. Four mutations in NS1 resulted in loss of binding to the host cleavage and polyadenylation specificity factor (CPSF30) suggesting that a reduction in inhibition of host gene expression was being selected. The most prevalent mutations in PB2 and NP were shown to increase virulence but differed in their ability to enhance replication and demonstrated epistatic effects. Several positively selected RNA polymerase mutations demonstrated increased virulence associated with >300% enhanced polymerase activity. Adaptive mutations that control host range and virulence were identified by their repeated selection to comprise a defined model for studying IAV evolution to increased virulence in the mouse.In vivo transfection of developmentally competent Brugia malayi infective larvae
AbstractXu, S., Liu, C., Tzertzinis, G., Ghedin, E., Evans, C. C., Kaplan, R., & Unnasch, T. R. (n.d.).Publication year
2011Journal title
International Journal for ParasitologyVolume
41Issue
3Page(s)
355-362AbstractTransient transfection of isolated Brugia malayi embryos by biolistics has proven to be useful in defining promoter structure and function in this parasite. However, isolated transfected embryos are developmentally incompetent. A method of producing developmentally competent transfected parasites is therefore needed. We report that L3 parasites can be chemically transfected in situ in the peritoneal cavity of a gerbil with a construct consisting of a secreted luciferase reporter gene containing a promoter, the 3′ untranslated region and first intron derived from the B. malayi 70. kDa heat shock protein gene. The in situ chemically transfected parasites are developmentally competent, producing adult parasites with an efficiency similar to that obtained from implanted untreated L3s. Cultured adult parasites and progeny microfilariae (mf) derived from L3s transfected with this construct secreted luciferase into the culture medium. When the transfected mf were fed to mosquitoes and the resulting L3s collected, the L3s also secreted luciferase into the culture medium. Progeny mf from transgenic adult parasites contained transgenic DNA, and the transgenic mRNA produced in these parasites was found to be correctly cis- and trans-spliced. In situ chemical transformation thus results in developmentally competent transfected B. malayi in which the transgenic sequences remain transcriptionally active in all life cycle stages and are present in the subsequent generation.Interaction of a Wolbachia WSP-like protein with a nuclear-encoded protein of Brugia malayi
AbstractMelnikow, E., Xu, S., Liu, J., Li, L., Oksov, Y., Ghedin, E., Unnasch, T. R., & Lustigman, S. (n.d.).Publication year
2011Journal title
International Journal for ParasitologyVolume
41Issue
10Page(s)
1053-1061AbstractThe Brugia malayi endosymbiont Wolbachia has recently been shown to be essential for its host's survival and development. However, relatively little is known about Wolbachia proteins that interact with the filarial host and which might be important in maintaining the obligate symbiotic relationship. The Wolbachia surface proteins (WSPs) are members of the outer membrane protein family and we hypothesise that they might be involved in the Wolbachia-. Brugia symbiotic relationship. Notably, immunolocalisation studies of two WSP members, WSP-0432 and WSP-0284 in B. malayi female adult worms showed that the corresponding proteins are not only present on the surface of Wolbachia but also in the host tissues, with WSP-0284 more abundant in the cuticle, hypodermis and the nuclei within the embryos. These results confirmed that WSPs might be secreted by Wolbachia into the worm's tissue. Our present studies focus on the potential involvement of WSP-0284 in the symbiotic relationship of Wolbachia with its filarial host. We show that WSP-0284 binds specifically to B. malayi crude protein extracts. Furthermore, a fragment of the hypothetical B. malayi protein (Bm1_46455) was found to bind WSP-0284 by panning of a B. malayi cDNA library. The interaction of WSP-0284 and this protein was further confirmed by ELISA and pull-down assays. Localisation by immunoelectron microscopy within Wolbachia cells as well as in the worm's tissues, cuticle and nuclei within embryos established that both proteins are present in similar locations within the parasite and the bacteria. Identifying such specific interactions between B. malayi and Wolbachia proteins should lead to a better understanding of the molecular basis of the filarial nematode and Wolbachia symbiosis.It's a small world after all - Viral genomics and the global dominance of viruses
Ghedin, E., & Upton, C. (n.d.).Publication year
2011Journal title
Current Opinion in VirologyVolume
1Issue
4Page(s)
280-281Molecular characterization of a new species in the genus Alphacoronavirus associated with mink epizootic catarrhal gastroenteritis
AbstractVlasova, A. N., Halpin, R., Wang, S., Ghedin, E., Spiro, D. J., & Saif, L. J. (n.d.).Publication year
2011Journal title
Journal of General VirologyVolume
92Issue
6Page(s)
1369-1379AbstractA coronavirus (CoV) previously shown to be associated with catarrhal gastroenteritis in mink (Mustela vison) was identified by electron microscopy in mink faeces from two fur farms in Wisconsin and Minnesota in 1998. A pan-coronavirus and a genus-specific RT-PCR assay were used initially to demonstrate that the newly discovered mink CoVs (MCoVs) were members of the genus Alphacoronavirus. Subsequently, using a random RT-PCR approach, full-genomic sequences were generated that further confirmed that, phylogenetically, the MCoVs belonged to the genus Alphacoronavirus, with closest relatedness to the recently identified but only partially sequenced (fragments of the polymerase, and full-length spike, 3c, envelope, nucleoprotein, membrane, 3x and 7b genes) ferret enteric coronavirus (FRECV) and ferret systemic coronavirus (FRSCV). The molecular data presented in this study provide the first genetic evidence for a new coronavirus associated with epizootic catarrhal gastroenteritis outbreaks in mink and demonstrate that MCoVs possess high genomic variability and relatively low overall nucleotide sequence identities (91.7%) between contemporary strains. Additionally, the new MCoVs appeared to be phylogenetically distant from human (229E and NL63) and other alphacoronaviruses and did not belong to the species Alphacoronavirus 1. It is proposed that, together with the partially sequenced FRECV and FRSCV, they comprise a new species within the genus Alphacoronavirus.Phylogeography of the spring and fall waves of the H1N1/09 pandemic influenza virus in the United States
AbstractNelson, M. I., Tan, Y., Ghedin, E., Wentworth, D. E., George, K. S., Edelman, L., Beck, E. T., Fan, J., Lam, T. T. Y., Kumar, S., Spiro, D. J., Simonsen, L., Viboud, C., Holmes, E. C., Henrickson, K. J., & Musser, J. M. (n.d.).Publication year
2011Journal title
Journal of virologyVolume
85Issue
2Page(s)
828-834AbstractSpatial variation in the epidemiological patterns of successive waves of pandemic influenza virus in humans has been documented throughout the 20th century but never understood at a molecular level. However, the unprecedented intensity of sampling and whole-genome sequencing of the H1N1/09 pandemic virus now makes such an approach possible. To determine whether the spring and fall waves of the H1N1/09 influenza pandemic were associated with different epidemiological patterns, we undertook a large-scale phylogeographic analysis of viruses sampled from three localities in the United States. Analysis of genomic and epidemiological data reveals distinct spatial heterogeneities associated with the first pandemic wave, March to July 2009, in Houston, TX, Milwaukee, WI, and New York State. In Houston, no specific H1N1/09 viral lineage dominated during the spring of 2009, a period when little epidemiological activity was observed in Texas. In contrast, major pandemic outbreaks occurred at this time in Milwaukee and New York State, each dominated by a different viral lineage and resulting from strong founder effects. During the second pandemic wave, beginning in August 2009, all three U.S. localities were dominated by a single viral lineage, that which had been dominant in New York during wave 1. Hence, during this second phase of the pandemic, extensive viral migration and mixing diffused the spatially defined population structure that had characterized wave 1, amplifying the one viral lineage that had dominated early on in one of the world's largest international travel centers.