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Department of Animal Sciences
The Robert H. Smith Faculty
of Agricultural, Food & Environment

The Hebrew University of Jerusalem.

P.O. Box 12, Rehovot 76100, Israel
Phone: +972-(0)8-9489119;
Fax: +972-(0)8-9465763;
Yael Lewitus, Department's Secretary
e-mail: yaellew@savion.huji.ac.il

Publications

2019
Embregts, C. W. E. ; Tadmor-Levi, R. ; Veselý, T. ; Pokorová, D. ; David, L. ; Wiegertjes, G. F. ; Forlenza, M. Intra-muscular and oral vaccination using a Koi Herpesvirus ORF25 DNA vaccine does not confer protection in common carp (Cyprinus carpio L.). Fish and Shellfish Immunology 2019, 85, 90-98. Publisher's VersionAbstract
Koi Herpes Virus (KHV or Cyprinid Herpesvirus 3, CyHV-3) is among the most threatening pathogens affecting common carp production as well as the highly valuable ornamental koi carp. To date, no effective commercial vaccine is available for worldwide use. A previous study reported that three intramuscular injections with an ORF25-based DNA vaccine, led to the generation of neutralizing antibodies and conferred significant protection against an intraperitoneal challenge with KHV. In the present study, we set out to optimize an ORF25-based DNA vaccination protocol that required fewer injections and would confer protection upon a challenge that better resembled the natural route of infection. To this end, ORF25 was cloned in pcDNA3 either as a soluble protein or as a full-length transmembrane GFP-fusion protein. We tested our ORF25-based DNA vaccines in multiple vaccination trials using different doses, vaccination routes (i.m. injection and oral gavage) and challenge methods (bath and cohabitation). Furthermore, we analysed local and systemic responses to the i.m. injected DNA vaccine through histological and RT-qPCR analysis. We observed a strong protection when fish received three injections of either of the two DNA vaccines. However, this protection was observed only after bath challenge and not after cohabitation challenge. Furthermore, protection was insufficient when fish received one injection only, or received the plasmid orally. The importance of choosing a challenge model that best reflects the natural route of infection and the possibility to include additional antigens in future DNA vaccination strategies against KHV will be discussed. © 2018 The Author(s)
Golani, D. ; Sonin, O. ; Snovsky, G. ; David, L. ; Tadmor-Levi, R. The occurrence of the peacock bass (Cichla kelberi Kullander and Ferreira, 2006) in Lake Kinneret (Sea of Galilee), Israel. BioInvasions Records 2019, 8 706-711. Publisher's VersionAbstract
A specimen of Cichla kelberi Kullander and Ferreira, 2006 was captured for the first time from Lake Kinneret (Sea of Galilee or Lake Tiberias), Israel. Its identification was made by morphological and molecular means. Although importation of this species to Israel is prohibited, commercial importers have smuggled juveniles as aquarium fish. The introduction vector of the specimen in Lake Kinneret is probably due to release or escape from the aquariums of hobbyists. © Golani et al.
Embregts, C. W. E. ; Tadmor-Levi, R. ; Veselý, T. ; Pokorová, D. ; David, L. ; Wiegertjes, G. F. ; Forlenza, M. Intra-muscular and oral vaccination using a Koi Herpesvirus ORF25 DNA vaccine does not confer protection in common carp (Cyprinus carpio L.). Fish & Shellfish Immunology 2019, 85, 90 - 98. Publisher's VersionAbstract
Koi Herpes Virus (KHV or Cyprinid Herpesvirus 3, CyHV-3) is among the most threatening pathogens affecting common carp production as well as the highly valuable ornamental koi carp. To date, no effective commercial vaccine is available for worldwide use. A previous study reported that three intramuscular injections with an ORF25-based DNA vaccine, led to the generation of neutralizing antibodies and conferred significant protection against an intraperitoneal challenge with KHV. In the present study, we set out to optimize an ORF25-based DNA vaccination protocol that required fewer injections and would confer protection upon a challenge that better resembled the natural route of infection. To this end, ORF25 was cloned in pcDNA3 either as a soluble protein or as a full-length transmembrane GFP-fusion protein. We tested our ORF25-based DNA vaccines in multiple vaccination trials using different doses, vaccination routes (i.m. injection and oral gavage) and challenge methods (bath and cohabitation). Furthermore, we analysed local and systemic responses to the i.m. injected DNA vaccine through histological and RT-qPCR analysis. We observed a strong protection when fish received three injections of either of the two DNA vaccines. However, this protection was observed only after bath challenge and not after cohabitation challenge. Furthermore, protection was insufficient when fish received one injection only, or received the plasmid orally. The importance of choosing a challenge model that best reflects the natural route of infection and the possibility to include additional antigens in future DNA vaccination strategies against KHV will be discussed.
Tadmor-Levi, R. ; Hulata, G. ; David, L. Multiple interacting QTLs affect disease challenge survival in common carp (Cyprinus carpio). Heredity 2019. Publisher's VersionAbstract
With the steady growth of the human population, food security becomes a prime challenge. Aquaculture is the fastest growing sector providing proteins from an animal source, but outbreaks of infectious diseases repeatedly hamper the production and further development of this sector. Breeding of disease-resistant strains is a desired sustainable solution to this problem. Cyprinid herpes virus-3 (CyHV-3) is a dsDNA virus damaging production of common carp, an important food and ornamental fish. Previously, we have demonstrated successful introgression of CyHV-3 resistance from a feral strain to commercial strains. Here, we used genotyping by sequencing to identify two novel quantitative trait loci (QTLs) for disease survival that map to different linkage groups than two other QTLs that we previously identified. Effects of these four QTLs were validated and further studied in 14 families with various levels of disease resistance. CyHV-3 survival was found to be a quantitative trait conditioned by mild additive QTL effects and by intricate dominant allelic and epistatic QTL–QTL interactions. Both rare feral alleles and alleles common to feral and cultured strains contributed to survival. This and other advantages of feral alleles introgression were demonstrated. These QTLs, which affected survival of individuals within families, had no significant effect on variation in cumulative family % survival, suggesting that more between family variation remains to be explored. Unraveling the underlying genetics of survival is important for enhancing the breeding of resistant strains and our knowledge of disease resistance mechanisms.
2018
Munang'andu, H. M. ; Galindo-Villegas, J. ; David, L. Teleosts Genomics: Progress and Prospects in Disease Prevention and Control. International journal of molecular sciences, 2018, 19. Publisher's Version
Mugimba, K. K. ; Chengula, A. A. ; Wamala, S. ; Mwega, E. D. ; Kasanga, C. J. ; Byarugaba, D. K. ; Mdegela, R. H. ; Tal, S. ; Bornstein, B. ; Dishon, A. ; et al. Detection of tilapia lake virus (TiLV) infection by PCR in farmed and wild Nile tilapia (Oreochromis niloticus) from Lake Victoria. Journal of Fish Diseases 2018, 41, 1181 - 1189. Publisher's VersionAbstract
Abstract Tilapia lake virus disease (TiLVD) has emerged to be an important viral disease of farmed Nile tilapia (Oreochromis niloticus) having the potential to impede expansion of aquaculture production. There is a need for rapid diagnostic tools to identify infected fish to limit the spread in individual farms. We report the first detection of TiLV infection by PCR in farmed and wild Nile tilapia from Lake Victoria. There was no difference in prevalence between farmed and wild fish samples (p = .65), and of the 442 samples examined from 191 fish, 28 were positive for TiLV by PCR. In terms of tissue distribution, the head kidney (7.69%, N = 65) and spleen (10.99%, N = 191), samples had the highest prevalence (p < .0028) followed by heart samples (3.45%, N = 29). Conversely, the prevalence was low in the liver (0.71%, N = 140) and absent in brain samples (0.0%, N = 17), which have previously been shown to be target organs during acute infections. Phylogenetic analysis showed homology between our sequences and those from recent outbreaks in Israel and Thailand. Given that these findings were based on nucleic acid detection by PCR, future studies should seek to isolate the virus from fish in Lake Victoria and show its ability to cause disease and virulence in susceptible fish.
Borovski, T. ; Tadmor-Levi, R. ; Shapiro, J. ; Rubinstein, G. ; Agyakwah, S. K. ; Hulata, G. ; David, L. Historical and recent reductions in genetic variation of the Sarotherodon galilaeus population in the Sea of Galilee. Conservation Genetics 2018, 19, 1323 - 1333. Publisher's VersionAbstract
The Sea of Galilee has great significance as a natural habitat and a freshwater source for Israel. Anthropogenic impacts have been placing significant pressure on the species inhabiting this lake, among which is Sarotherodon galilaeus, an omnivorous fish with a relatively large population and significance for commercial fishing. An alarming decline in annual catch towards 2008 suggested that this unique population might be at risk. With that in mind, we characterized the current genetic variation of this species in Israel with reference to fish from Ghana, based on D-loop and microsatellite markers. Genetic variation and differentiation were found mostly among fish from Ghanaian localities and between fish from Israel and Ghana, whereas fish from all Israeli localities had uniform and limited variation, a signature compatible with historical founder effect followed by local adaptations. Such historical processes could leave a population vulnerable as reflected in the sudden and recent population decline. Comparing genetic variation between archived 30 year-old scales and modern lake fish revealed further reduction in genetic variation coincident with the recent population decline. Thus, a recently occurring genetic bottleneck had placed this unique and isolated population at an even higher risk. We carefully discuss the events leading to the current risk status for S. galilaeus in Israel and highlight the need for vigilant monitoring and active management to support a more sustainable future for this and other fish communities in this important habitat.
Yasur-Landau, D. ; Jaffe, C. L. ; David, L. ; Doron-Faigenboim, A. ; Baneth, G. Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number. Includes articles from the scientific meeting: "Anthelmintics: From Discovery to Resistance III", pp. 494-628 2018, 8 403 - 410. Publisher's VersionAbstract
Leishmania infantum is one of the causative agents of visceral leishmaniasis (VL), a widespread, life-threatening disease. This parasite is responsible for the majority of human VL cases in Brazil, the Middle East, China, Central Asia and the Mediterranean basin. Its main reservoir are domestic dogs which, similar to human patients, may develop severe visceral disease and die if not treated. The drug allopurinol is used for the long-term maintenance of dogs with canine leishmaniasis. Following our report of allopurinol resistance in treated relapsed dogs, we investigated the mechanisms and markers of resistance to this drug. Whole genome sequencing (WGS) of clinical resistant and susceptible strains, and laboratory induced resistant parasites, was carried out in order to detect genetic changes associated with resistance. Significant gene copy number variation (CNV) was found between resistant and susceptible isolates at several loci, including a locus on chromosome 30 containing the genes LinJ.30.3550 through LinJ.30.3580. A reduction in copy number for LinJ.30.3560, encoding the S-adenosylmethionine synthetase (METK) gene, was found in two resistant clinical isolates and four induced resistant clonal strains. Using quantitative real time PCR, this reduction in METK copy number was also found in three additional resistant clinical isolates. Furthermore, inhibition of S-adenosylmethionine synthetase encoded by the METK gene in allopurinol susceptible strains resulted in increased allopurinol resistance, confirming its role in resistance to allopurinol. In conclusion, this study identified genetic changes associated with L. infantum resistance to allopurinol and the reduction in METK copy number identified may serve as a marker for resistance in dogs, and reduced protein activity correlated with increased allopurinol resistance.
2017
Tadmor-Levi, R. ; Asoulin, E. ; Hulata, G. ; David, L. Studying the Genetics of Resistance to CyHV-3 Disease Using Introgression from Feral to Cultured Common Carp Strains. Frontiers in Genetics 2017, 8 24. Publisher's VersionAbstract
Sustainability and further development of aquaculture production are constantly challenged by outbreaks of fish diseases, which are difficult to prevent or control. Developing fish strains that are genetically resistant to a disease is a cost-effective and a sustainable solution to address this challenge. To do so, heritable genetic variation in disease resistance should be identified and combined together with other desirable production traits. Aquaculture of common carp has suffered substantial losses from the infectious disease caused by the cyprinid herpes virus type 3 (CyHV-3) virus and the global spread of outbreaks indicates that many cultured strains are susceptible. In this research, CyHV-3 resistance from the feral strain “Amur Sassan” was successfully introgressed into two susceptible cultured strains up to the first backcross (BC1) generation. Variation in resistance of families from F1 and BC1 generations was significantly greater compared to that among families of any of the susceptible parental lines, a good starting point for a family selection program. Considerable additive genetic variation was found for CyHV-3 resistance. This phenotype was transferable between generations with contributions to resistance from both the resistant feral and the susceptible cultured strains. Reduced scale coverage (mirror phenotype) is desirable and common in cultured strains, but so far, cultured mirror carp strains were found to be susceptible. Here, using BC1 families ranging from susceptible to resistant, no differences in resistance levels between fully scaled and mirror full-sib groups were found, indicating that CyHV-3 resistance was successfully combined with the desirable mirror phenotype. In addition, the CyHV-3 viral load in tissues throughout the infection of susceptible and resistant fish was followed. Although resistant fish get infected, viral loads in tissues of these fish are significantly lesser than in those of susceptible fish, allowing them to survive the disease. Taken together, in this study we have laid the foundation for breeding CyHV-3-resistant strains and started to address the mechanisms underlying the phenotypic differences in resistance to this disease.
Yasur-Landau, D. ; Jaffe, C. L. ; Doron-Faigenboim, A. ; David, L. ; Baneth, G. Induction of allopurinol resistance in Leishmania infantum isolated from dogs. PLOS Neglected Tropical Diseases 2017, 11, 1-10. Publisher's VersionAbstract
Author summary Visceral leishmaniasis caused by the parasite Leishmania infantum is a neglected tropical disease transmitted from animal hosts to humans by sand fly bites. This potentially fatal disease affects thousands of people annually and threatens millions who live in disease risk areas. Domestic dogs are considered as the main reservoir of this parasite which can also cause a severe chronic canine disease. Allopurinol is the main drug used for long term treatment of this disease but it often does not eliminate infection in dogs. We have recently demonstrated that allopurinol resistant parasites can be isolated from naturally infected dogs that have developed clinical recurrence of disease during allopurinol treatment. In this study we aimed to see if resistance can be induced in susceptible parasite strains isolated from sick dogs by growing them in increasing drug concentrations under laboratory conditions. The changes in allopurinol susceptibility were measured and the impact of drug on parasite growth was monitored over 23 weeks. Induction of resistance was successful producing parasites 20-folds less susceptible to the drug. The pattern of change in drug susceptibility suggests that a genetic change is responsible for the increased resistance which is likely to mimic the formation of resistance in dogs.
Petit, J. ; David, L. ; Dirks, R. ; Wiegertjes, G. F. Genomic and transcriptomic approaches to study immunology in cyprinids: What is next?. Developmental & Comparative Immunology 2017, 75, 48 - 62. Publisher's VersionAbstract
Accelerated by the introduction of Next-Generation Sequencing (NGS), a number of genomes of cyprinid fish species have been drafted, leading to a highly valuable collective resource of comparative genome information on cyprinids (Cyprinidae). In addition, NGS-based transcriptome analyses of different developmental stages, organs, or cell types, increasingly contribute to the understanding of complex physiological processes, including immune responses. Cyprinids are a highly interesting family because they comprise one of the most-diversified families of teleosts and because of their variation in ploidy level, with diploid, triploid, tetraploid, hexaploid and sometimes even octoploid species. The wealth of data obtained from NGS technologies provides both challenges and opportunities for immunological research, which will be discussed here. Correct interpretation of ploidy effects on immune responses requires knowledge of the degree of functional divergence between duplicated genes, which can differ even between closely-related cyprinid fish species. We summarize NGS-based progress in analysing immune responses and discuss the importance of respecting the presence of (multiple) duplicated gene sequences when performing transcriptome analyses for detailed understanding of complex physiological processes. Progressively, advances in NGS technology are providing workable methods to further elucidate the implications of gene duplication events and functional divergence of duplicates genes and proteins involved in immune responses in cyprinids. We conclude with discussing how future applications of NGS technologies and analysis methods could enhance immunological research and understanding.
2016
Yasur-Landau, D. ; Jaffe, C. L. ; David, L. ; Baneth, G. Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse. PLoS Neglected Tropical Diseases 2016, 10. Publisher's Version
Wiegertjes, G. F. ; Lorenzen, N. ; Secombes, C. J. ; Collet, B. ; Fischer, U. ; Tafalla, C. ; Parra, D. ; Scapigliati, G. ; Boudinot, P. ; Evensen, Ø. ; et al. TargetFish - Targeted disease prophylaxis in European fish farming. Bulletin of the European Association of Fish Pathologists 2016, 36, 52 - 56. Publisher's Version
Shapira, R. ; David, L. Genes with a Combination of Over-Dominant and Epistatic Effects Underlie Heterosis in Growth of Saccharomyces cerevisiae at High Temperature. Frontiers in Genetics 2016, 7 72. Publisher's VersionAbstract
Heterosis describes a phenotypic phenomenon of hybrid superiority over its homozygous parents. It is a genetically intriguing phenomenon with great importance for food production. Also called hybrid-vigor, heterosis is created by non-additive effects of genes in a heterozygous hybrid made by crossing two distinct homozygous parents. Few models have been proposed to explain how the combination of parental genes creates an exceptional hybrid performance. Over-dominant mode of inheritance is an attractive model since a single gene can potentially create the heterotic effect, but only a few such loci have been identified. To a collection of 120 hybrids, made by crossing 16 divergent Saccharomyces cerevisiae yeast strains, we applied a method for mapping heterozygous loci that non-additively contribute to heterotic growth at 37°. Among 803 candidate loci that were mapped, five were tested for their heterotic effect by analyzing backcrosses and F2 populations in a specific hybrid background. Consistently with the many mapped loci, specific analyses confirmed the minor heterotic effect of the tested candidate loci. Allele-replacement analyses of one gene, AEP3, further supported its heterotic effect. In addition to over-dominant effects, the contribution of epistasis to heterosis was evident from F2 population and allele-replacement analyses. Pairs of over-dominant genes contributed synergistically to heterosis. We show that minor over-dominant effects of multiple genes can combine to condition heterosis, similarly to loci affecting other quantitative traits. Furthermore, by finding of epistatic interactions between loci that each of them individually has an over-dominant effect on heterosis, we demonstrate how hybrid advantage could benefit from a synergistic combination of two interaction types (over-dominant and synergistic epistatic). Thus, by portraying the underlying genetic complexity, these findings advance our understanding of heterosis.