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1. Using CRISPR/Cas9 to model human liver disease

Author

Michele Alves-Bezerra, Nika Furey, Collin G. Johnson, and Karl-Dimiter Bissig

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Summary: CRISPR/Cas9 gene editing has revolutionised biomedical research. The ease of design has allowed many groups to apply this technology for disease modelling in animals. While the mouse remains the most commonly used organism for embryonic editing, CRISPR is now increasingly performed with high efficiency in other species. The liver is also amenable to somatic genome editing, and some delivery methods already allow for efficient editing in the whole liver. In this review, we describe CRISPR-edited animals developed for modelling a broad range of human liver disorders, such as acquired and inherited hepatic metabolic diseases and liver cancers. CRISPR has greatly expanded the repertoire of animal models available for the study of human liver disease, advancing our understanding of their pathophysiology and providing new opportunities to develop novel therapeutic approaches.

Published
2019
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2. A human liver chimeric mouse model for non-alcoholic fatty liver disease

Author

Beatrice Bissig-Choisat, Michele Alves-Bezerra, Barry Zorman, Scott A. Ochsner, Mercedes Barzi, Xavier Legras, Diane Yang, Malgorzata Borowiak, Adam M. Dean, Robert B. York, N. Thao N. Galvan, John Goss, William R. Lagor, David D. Moore, David E. Cohen, Neil J. McKenna, Pavel Sumazin, and Karl-Dimiter Bissig

Subjects
Non-alcoholic fatty liver disease, Steatosis, Lipid metabolism, Human disease modelling, Humanised mice, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: The accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world’s population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model. Methods: We generated TIRF (transgene-free Il2rg-/-/Rag2-/-/Fah-/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks. Results: Within the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis. Conclusions: These NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis. Lay summary: Fatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.

Published
2021
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3. Maternal Programming of Social Dominance via Milk Cytokines

Author

Faten Taki, Katherine Lopez, Bojana Zupan, Paul Bergin, Melissa D. Docampo, Michele Alves-Bezerra, Judit Gal Toth, Qiuying Chen, Kimon V. Argyropoulos, Luendreo Barboza, Emily Pickup, Nicholas Fancher, Abbi Hiller, Steven Gross, David E. Cohen, Marcel R.M. van den Brink, and Miklos Toth

Subjects
Biological Sciences, Behavioral Neuroscience, Immunology, Science
Abstract

Summary: Regular physical activity improves physical and mental health. Here we found that the effect of physical activity extends to the next generation. Voluntary wheel running of dams, from postpartum day 2 to weaning, increased the social dominance and reproductive success, but not the physical/metabolic health, of their otherwise sedentary offspring. The individual's own physical activity did not improve dominance status. Maternal exercise did not disrupt maternal care or the maternal and offspring microbiota. Rather, the development of dominance behavior in the offspring of running mothers could be explained by the reduction of LIF, CXCL1, and CXCL2 cytokines in breast milk. These data reveal a cytokine-mediated lactocrine pathway that responds to the mother's postpartum physical activity and programs offspring social dominance. As dominance behaviors are highly relevant to the individual's survival and reproduction, lactocrine programming could be an evolutionary mechanism by which a mother promotes the social rank of her offspring.

Published
2020
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4. Regulation of fatty acid trafficking in liver by thioesterase superfamily member 1

Author

Anal Desai, Michele Alves-Bezerra, Yingxia Li, Cafer Ozdemir, Curtis J. Bare, Yue Li, Susan J. Hagen, and David E. Cohen

Subjects
lipids, nonalcoholic fatty liver disease, obesity, triglycerides, fatty acid/metabolism, fatty acid/oxidation, Biochemistry, QD415-436
Abstract

Thioesterase superfamily member 1 (Them1) is an acyl-CoA thioesterase that is highly expressed in brown adipose tissue, where it functions to suppress energy expenditure. Lower Them1 expression levels in the liver are upregulated in response to high-fat feeding. Them1−/− mice are resistant to diet-induced obesity, hepatic steatosis, and glucose intolerance, but the contribution of Them1 in liver is unclear. To examine its liver-specific functions, we created conditional transgenic mice, which, when bred to Them1−/− mice and activated, expressed Them1 exclusively in the liver. Mice with liver-specific Them1 expression exhibited no changes in energy expenditure. Rates of fatty acid oxidation were increased, whereas hepatic VLDL triglyceride secretion rates were decreased by hepatic Them1 expression. When fed a high-fat diet, Them1 expression in liver promoted excess steatosis in the setting of reduced rates of fatty acid oxidation and preserved glycerolipid synthesis. Liver-specific Them1 expression did not influence glucose tolerance or insulin sensitivity, but did promote hepatic gluconeogenesis in high-fat-fed animals. This was attributable to the generation of excess fatty acids, which activated PPARα and promoted expression of gluconeogenic genes. These findings reveal a regulatory role for Them1 in hepatocellular fatty acid trafficking.

Published
2018
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5. An insight into the transcriptome of the digestive tract of the bloodsucking bug, Rhodnius prolixus.

Author

José M C Ribeiro, Fernando A Genta, Marcos H F Sorgine, Raquel Logullo, Rafael D Mesquita, Gabriela O Paiva-Silva, David Majerowicz, Marcelo Medeiros, Leonardo Koerich, Walter R Terra, Clélia Ferreira, André C Pimentel, Paulo M Bisch, Daniel C Leite, Michelle M P Diniz, João Lídio da S G V Junior, Manuela L Da Silva, Ricardo N Araujo, Ana Caroline P Gandara, Sébastien Brosson, Didier Salmon, Sabrina Bousbata, Natalia González-Caballero, Ariel Mariano Silber, Michele Alves-Bezerra, Katia C Gondim, Mário Alberto C Silva-Neto, Georgia C Atella, Helena Araujo, Felipe A Dias, Carla Polycarpo, Raquel J Vionette-Amaral, Patrícia Fampa, Ana Claudia A Melo, Aparecida S Tanaka, Carsten Balczun, José Henrique M Oliveira, Renata L S Gonçalves, Cristiano Lazoski, Rolando Rivera-Pomar, Luis Diambra, Günter A Schaub, Elói S Garcia, Patrícia Azambuja, Glória R C Braz, and Pedro L Oliveira

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

The bloodsucking hemipteran Rhodnius prolixus is a vector of Chagas' disease, which affects 7-8 million people today in Latin America. In contrast to other hematophagous insects, the triatomine gut is compartmentalized into three segments that perform different functions during blood digestion. Here we report analysis of transcriptomes for each of the segments using pyrosequencing technology. Comparison of transcript frequency in digestive libraries with a whole-body library was used to evaluate expression levels. All classes of digestive enzymes were highly expressed, with a predominance of cysteine and aspartic proteinases, the latter showing a significant expansion through gene duplication. Although no protein digestion is known to occur in the anterior midgut (AM), protease transcripts were found, suggesting secretion as pro-enzymes, being possibly activated in the posterior midgut (PM). As expected, genes related to cytoskeleton, protein synthesis apparatus, protein traffic, and secretion were abundantly transcribed. Despite the absence of a chitinous peritrophic membrane in hemipterans - which have instead a lipidic perimicrovillar membrane lining over midgut epithelia - several gut-specific peritrophin transcripts were found, suggesting that these proteins perform functions other than being a structural component of the peritrophic membrane. Among immunity-related transcripts, while lysozymes and lectins were the most highly expressed, several genes belonging to the Toll pathway - found at low levels in the gut of most insects - were identified, contrasting with a low abundance of transcripts from IMD and STAT pathways. Analysis of transcripts related to lipid metabolism indicates that lipids play multiple roles, being a major energy source, a substrate for perimicrovillar membrane formation, and a source for hydrocarbons possibly to produce the wax layer of the hindgut. Transcripts related to amino acid metabolism showed an unanticipated priority for degradation of tyrosine, phenylalanine, and tryptophan. Analysis of transcripts related to signaling pathways suggested a role for MAP kinases, GTPases, and LKBP1/AMP kinases related to control of cell shape and polarity, possibly in connection with regulation of cell survival, response of pathogens and nutrients. Together, our findings present a new view of the triatomine digestive apparatus and will help us understand trypanosome interaction and allow insights into hemipteran metabolic adaptations to a blood-based diet.

Published
2014
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6. A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Author

Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wong, Vincent Wai-Sun, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Newsome, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, Shira Zelber-Sagi, Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, and Vincent Wai-Sun, W

Subjects
steatotic liver disease, MASLD, alcohol, steatohepatiti, MetALD, NASH, nonalcoholic, Delphi, Fatty liver disease, NAFLD, cardiometabolic, nomenclature, mafld, type 2 diabetes, MED/13 - ENDOCRINOLOGIA
Abstract

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350g/week and 210 to 420g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

Published
2023

7. Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection

Author

Carla Polycarpo, Magda D. Lugon, Emmanuelle Jacquin-Joly, Francisco Prosdocimi, Katia C. Gondim, Daniel Lawson, Raquel J. Vionette-Amaral, Karyn Megy, Andrew Pike, Fernando A. Monteiro, David Majerowicz, Marco Mariotti, Gloria I. Giraldo-Calderón, Fernando G. Noriega, Ana Beatriz Walter-Nuno, M. Patricia Juárez, Leonardo Koerich, A. Bernardo Carvalho, Marcos Sterkel, Fernando Abad-Franch, Catrina Fronick, Samara G. da Costa, Eloy S. Seabra-Junior, Márcio G. Pavan, Pedro L. Oliveira, Willy Jablonka, Myriam Harry, Ana C.A. Melo, Rita D. Fernandez-Medina, George Dimopoulos, Igor Rodrigues da Costa, Cristiano Lazoski, Alessandra A. Guarneri, Paula L. Marcet, Lucinda Fulton, Gena G. Lawrence, Patrícia Azambuja, Gabriela O. Paiva-Silva, Adriana Granzotto, Francisco Panzera, Marcelo G. Lorenzo, Didac Santesmasses, Raquel L.L. Oliveira, Ricardo Nascimento Araújo, Hugh M. Robertson, Renata Schama, Matheus Souza-Gomes, Didier Salmon, Iron F. De-Paula, José M. C. Ribeiro, Roderic Guigó, Derek Wilson, Ana Caroline P. Gandara, Rolando Rivera-Pomar, André Q. Torres, Raul Ursic-Bedoya, Andrés Lavore, Scott J. Emrich, Marcio Fontenele, Laurence Rodrigues do Amaral, Felipe A. Dias, Mário A.C. Silva-Neto, Claudia M. A. Carareto, John Spieth, Nicolás Pedrini, Erwin Huebner, Claudio R. Lazzari, Rafael D. Mesquita, Helena Araujo, Ian Orchard, Fernando A. Genta, Daniel S.T. Hughes, Zhijian Jake Tu, Carl Lowenberger, Paula R. Bittencourt-Cunha, Marcos Henrique Ferreira Sorgine, Michael J. Montague, Rodrigo Nunes da Fonseca, Gustavo M. Calderón-Fernández, Alexandre A. Peixoto, Marcela Nouzova, Angela B. Lange, Gilbert Oliveira-Silveira, Eloi S. Garcia, L. Aravind, Ellen M. Dotson, Hatisaburo Masuda, Glória R.C. Braz, Bruno Gomes, Natalia Esponda-Behrens, Raphael R.S. Lopes, Marilvia Dansa, Sheila Ons, Patrícia Fampa, Rodrigo Dutra Nunes, Mikkel B. Christensen, Ana Paula Salerno, Mabel L. Taracena, Marta Tojo, Georgia C. Atella, Jose Manuel Latorre-Estivalis, Marcos H. Pereira, Agustina Pascual, Michele Alves-Bezerra, Robert M. Waterhouse, Theo Mota, Rodrigo Ribeiro-Rodrigues, Thiago M. Venancio, Lucia Pagola, Fanis Missirlis, Carlos R. O. Daumas-Filho, Jose M. C. Tubio, Lívia Silva-Cardoso, Wesley C. Warren, Richard K. Wilson, Patrick Minx, Mateus Berni, Mesquita, Rafael D., Vionette Amaral, Raquel J., Departamento de Bioquimica, UNICAMP, Institut de recherche sur la biologie de l'insecte UMR7261 (IRBI), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health Grant [NHGRI-HG003079], National Institutes of Health National Institute of Allergy and Infectious Diseases Grant [HHSN272200900039C], Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Fundacao de Amparo a Pesquisa do Estado de Minas Gerais, Consejo Nacional de Investigaciones Cientificas y Tecnicas de Argentina, Agencia Nacional de Promocion de Ciencia y Tecnologia, Fundacion Bunge y Born, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/FAPERJ, [PIOF-GA-2011-303312], and Université de Tours-Centre National de la Recherche Scientifique (CNRS)

Subjects
0106 biological sciences, Chagas disease, Biología, [SDV]Life Sciences [q-bio], ved/biology.organism_classification_rank.species, maladie de chagas, 01 natural sciences, Genome, purl.org/becyt/ford/1 [https], rhodnius prolixus, Putative gene, ddc:576.5, Genetics, 0303 health sciences, Multidisciplinary, Host-Parasite Interactions/genetics, RHODNIUS PROLIXUS, Ecology, Trypanosoma cruzi/physiology, Adaptation, Physiological/genetics, Biological Sciences, 3. Good health, GENOME, Wolbachia, Wolbachia/genetics, Gene Transfer, Horizontal, hematophagy, Hematophagy, Rhodnius, Molecular Sequence Data, Rhodnius prolixus, genome, immunity, Biology, IMMUNITY, 010603 evolutionary biology, 03 medical and health sciences, Animals, Humans, Model organism, purl.org/becyt/ford/1.6 [https], Gene, Rhodnius/genetics/parasitology, 030304 developmental biology, Base Sequence, ved/biology, CHAGAS DISEASE, biology.organism_classification, Insect Vectors/genetics/parasitology, HEMATOPHAGY
Abstract

Rhodnius prolixus not only has served as a model organism for the study of insect physiology, but also is a major vector of Chagas disease, an illness that affects approximately seven million people worldwide. We sequenced the genome of R. prolixus, generated assembled sequences covering 95% of the genome (∼702 Mb), including 15,456 putative protein-coding genes, and completed comprehensive genomic analyses of this obligate blood-feeding insect. Although immunedeficiency (IMD)-mediated immune responses were observed, R. prolixus putatively lacks key components of the IMD pathway, suggesting a reorganization of the canonical immune signaling network. Although both Toll and IMD effectors controlled intestinal microbiota, neither affected Trypanosoma cruzi, the causal agent of Chagas disease, implying the existence of evasion or tolerance mechanisms. R. prolixus has experienced an extensive loss of selenoprotein genes, with its repertoire reduced to only two proteins, one of which is a selenocysteine-based glutathione peroxidase, the first found in insects. The genome contained actively transcribed, horizontally transferred genes from Wolbachia sp., which showed evidence of codon use evolution toward the insect use pattern. Comparative protein analyses revealed many lineage-specific expansions and putative gene absences in R. prolixus, including tandem expansions of genes related to chemoreception, feeding, and digestion that possibly contributed to the evolution of a blood-feeding lifestyle. The genome assembly and these associated analyses provide critical information on the physiology and evolution of this important vector species and should be instrumental for the development of innovative disease control methods., La lista completa de autores que integran el documento puede consultarse en el archivo, Este documento tiene una corrección (ver documento relacionado)., Centro Regional de Estudios Genómicos, Instituto de Investigaciones Bioquímicas de La Plata

Published
2015
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8. An Insight into the Transcriptome of the Digestive Tract of the Bloodsucking Bug, Rhodnius prolixus

Author

Günter A. Schaub, Marcos Henrique Ferreira Sorgine, Sébastien Brosson, Patrícia Fampa, Walter R. Terra, Helena Araujo, Pedro L. Oliveira, José M. C. Ribeiro, Cristiano Lazoski, Patrícia Azambuja, Katia C. Gondim, Raquel Logullo, Ricardo Nascimento Araújo, João Galan Júnior, Gabriela O. Paiva-Silva, Jose Henrique M. Oliveira, André C. Pimentel, Marcelo N. Medeiros, Ana Caroline P. Gandara, Daniel Leite, Renata L.S. Goncalves, Sabrina Bousbata, Carla Polycarpo, Manuela Leal da Silva, Ana C.A. Melo, Rolando Rivera-Pomar, Georgia C. Atella, Michele Alves-Bezerra, Glória R.C. Braz, Mário A.C. Silva-Neto, Rafael D. Mesquita, Fernando A. Genta, Didier Salmon, Aparecida S. Tanaka, Eloi S. Garcia, Paulo Mascarello Bisch, Luis Aníbal Diambra, Ariel Mariano Silber, Felipe A. Dias, Clélia Ferreira, Carsten Balczun, Raquel J. Vionette-Amaral, Leonardo Koerich, David Majerowicz, Natalia González-Caballero, and Michelle M. P. Diniz

Subjects
Male, Anatomy and Physiology, Digestive Physiology, Bioinformatics, TRIATOMINAE, ANNOTATION, Transcriptome, purl.org/becyt/ford/1 [https], TRANSCRIPTOMIC, DIGESTIVE TRACT, Triatoma, Parasitologie, biology, RHODNIUS PROLIXUS, lcsh:Public aspects of medicine, Genomics, Bioquímica y Biología Molecular, Cell biology, Functional Genomics, Infectious Diseases, Rhodnius, Medicine, Insect Proteins, Female, Energy source, Biologie, Sequence Analysis, CIENCIAS NATURALES Y EXACTAS, Research Article, Neglected Tropical Diseases, Chagas’ disease, lcsh:Arctic medicine. Tropical medicine, Protein digestion, lcsh:RC955-962, Trypanosoma cruzi, Molecular Sequence Data, Sciences de la matière vivante, Ciencias Biológicas, Animals, Secretion, Chagas Disease, Rhodnius prolixus, purl.org/becyt/ford/1.6 [https], Biology, Ciencias Exactas, Digestive Functions, Digestive Regulation, Public Health, Environmental and Occupational Health, Computational Biology, Midgut, lcsh:RA1-1270, Vectors and Hosts, Sequence Analysis, DNA, biology.organism_classification, Gastrointestinal Tract, Latin America, Membrane protein, Digestive System, Zoology, Entomology
Abstract

The bloodsucking hemipteran Rhodnius prolixus is a vector of Chagas' disease, which affects 7-8 million people today in Latin America. In contrast to other hematophagous insects, the triatomine gut is compartmentalized into three segments that perform different functions during blood digestion. Here we report analysis of transcriptomes for each of the segments using pyrosequencing technology. Comparison of transcript frequency in digestive libraries with a whole-body library was used to evaluate expression levels. All classes of digestive enzymes were highly expressed, with a predominance of cysteine and aspartic proteinases, the latter showing a significant expansion through gene duplication. Although no protein digestion is known to occur in the anterior midgut (AM), protease transcripts were found, suggesting secretion as pro-enzymes, being possibly activated in the posterior midgut (PM). As expected, genes related to cytoskeleton, protein synthesis apparatus, protein traffic, and secretion were abundantly transcribed. Despite the absence of a chitinous peritrophic membrane in hemipterans - which have instead a lipidic perimicrovillar membrane lining over midgut epithelia - several gut-specific peritrophin transcripts were found, suggesting that these proteins perform functions other than being a structural component of the peritrophic membrane. Among immunity-related transcripts, while lysozymes and lectins were the most highly expressed, several genes belonging to the Toll pathway - found at low levels in the gut of most insects - were identified, contrasting with a low abundance of transcripts from IMD and STAT pathways. Analysis of transcripts related to lipid metabolism indicates that lipids play multiple roles, being a major energy source, a substrate for perimicrovillar membrane formation, and a source for hydrocarbons possibly to produce the wax layer of the hindgut. Transcripts related to amino acid metabolism showed an unanticipated priority for degradation of tyrosine, phenylalanine, and tryptophan. Analysis of transcripts related to signaling pathways suggested a role for MAP kinases, GTPases, and LKBP1/AMP kinases related to control of cell shape and polarity, possibly in connection with regulation of cell survival, response of pathogens and nutrients. Together, our findings present a new view of the triatomine digestive apparatus and will help us understand trypanosome interaction and allow insights into hemipteran metabolic adaptations to a blood-based diet., Journal Article, Research Support, N.I.H. Intramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

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