Babesia duncani multi-omics identifies virulence factors and drug targets
Por:
Singh, Pallavi, Lonardi, Stefano, Liang, Qihua, Vydyam, Pratap, Khabirova, Eleonora, Fang, Tiffany, Gihaz, Shalev, Thekkiniath, Jose, Munshi, Muhammad, Abel, Steven, Ciampossin, Loic, Batugedara, Gayani, Gupta, Mohit, Lu, Xueqing Maggie, Lenz, Todd, Chakravarty, Sakshar, Cornillot, Emmanuel, Hu, Yangyang, Ma, Wenxiu, Gonzalez, Luis Miguel, Sanchez, Sergio, Estrada, Karel, Sanchez-Flores, Alejandro, Montero, Estrella, Harb, Omar S., Le Roch, Karine G., Mamoun C.B.
Publicada:
1 may 2023
Ahead of Print:
1 abr 2023
Resumen:
Babesiosis is a malaria-like disease in humans and animals that is
caused by Babesia species, which are tick-transmitted apicomplexan
pathogens. Babesia duncani causes severe to lethal infection in humans,
but despite the risk that this parasite poses as an emerging pathogen,
little is known about its biology, metabolic requirements or
pathogenesis. Unlike other apicomplexan parasites that infect red blood
cells, B. duncani can be continuously cultured in vitro in human
erythrocytes and can infect mice resulting in fulminant babesiosis and
death. We report comprehensive, detailed molecular, genomic,
transcriptomic and epigenetic analyses to gain insights into the biology
of B. duncani. We completed the assembly, 3D structure and annotation of
its nuclear genome, and analysed its transcriptomic and epigenetics
profiles during its asexual life cycle stages in human erythrocytes. We
used RNA-seq data to produce an atlas of parasite metabolism during its
intraerythrocytic life cycle. Characterization of the B. duncani genome,
epigenome and transcriptome identified classes of candidate virulence
factors, antigens for diagnosis of active infection and several
attractive drug targets. Furthermore, metabolic reconstitutions from
genome annotation and in vitro efficacy studies identified antifolates,
pyrimethamine and WR-99210 as potent inhibitors of B. duncani to
establish a pipeline of small molecules that could be developed as
effective therapies for the treatment of human babesiosis.
Comprehensive multi-omics of Babesia duncani reveals evolution, drug
sensitivity and virulence.
Filiaciones:
Singh, Pallavi:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Lonardi, Stefano:
Department of Computer Science and Engineering, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Comp Sci & Engn, Riverside, CA 92521 USA
Liang, Qihua:
Department of Computer Science and Engineering, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Comp Sci & Engn, Riverside, CA 92521 USA
Vydyam, Pratap:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Khabirova, Eleonora:
Department of Statistics, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Stat, Riverside, CA USA
Fang, Tiffany:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Gihaz, Shalev:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Thekkiniath, Jose:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Munshi, Muhammad:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT 06510 USA
Abel, Steven:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Ciampossin, Loic:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Batugedara, Gayani:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Gupta, Mohit:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Lu, Xueqing Maggie:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Lenz, Todd:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Chakravarty, Sakshar:
Department of Computer Science and Engineering, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Comp Sci & Engn, Riverside, CA 92521 USA
Cornillot, Emmanuel:
Institut de Biologie Computationnelle (IBC), and Institut de Recherche en Cancérologie de Montpellier (IRCM - INSERM U1194), Institut régional du Cancer Montpellier (ICM) and Université de Montpellier, Montpellier, France
Univ Montpellier, Inst Biol Computat IBC, Montpellier, France
Inst reg Canc Montpellier ICM, Inst Rech Cancerol Montpellier IRCM, INSERM U1194, Montpellier, France
Univ Montpellier, Montpellier, France
Hu, Yangyang:
Department of Computer Science and Engineering, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Comp Sci & Engn, Riverside, CA 92521 USA
Ma, Wenxiu:
Department of Statistics, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Stat, Riverside, CA USA
Gonzalez, Luis Miguel:
Parasitology Reference and Research Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
Inst Salud Carlos III, Parasitol Reference & Res Lab, Natl Ctr Microbiol, Madrid, Spain
Sanchez, Sergio:
Reference and Research Laboratory on Food and Waterborne Bacterial Infections, National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
Inst Salud Carlos III, Reference & Res Lab Food & Waterborne Bacterial I, Natl Ctr Microbiol, Majadahonda, Madrid, Spain
Estrada, Karel:
Unidad Universitaria de Secuenciación Masiva y Bioinformática, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
Univ Nacl Autonoma Mexico, Unidad Univ Secuenciac Mas & Bioinformat, Inst Biotecnol, Cuernavaca, Mexico
Sanchez-Flores, Alejandro:
Unidad Universitaria de Secuenciación Masiva y Bioinformática, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
Univ Nacl Autonoma Mexico, Unidad Univ Secuenciac Mas & Bioinformat, Inst Biotecnol, Cuernavaca, Mexico
Montero, Estrella:
Parasitology Reference and Research Laboratory, National Centre for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
Inst Salud Carlos III, Parasitol Reference & Res Lab, Natl Ctr Microbiol, Madrid, Spain
Harb, Omar S.:
Department of Biology, University of Pennsylvania, Philadelphia, PA, United States
Univ Penn, Dept Biol, Philadelphia, PA USA
Le Roch, Karine G.:
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, United States
Univ Calif Riverside, Dept Mol Cell & Syst Biol, Riverside, CA 92521 USA
Mamoun C.B.:
Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, United States
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