Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum
ABSTRACT Transmission of the deadly malaria parasite Plasmodium falciparum from humans to mosquitoes is achieved by specialized intraerythrocytic sexual forms called gametocytes. Though the crucial regulatory mechanisms leading to gametocyte commitment have recently come to light, networks of genes...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.04164-22 |
| _version_ | 1797803499707170816 |
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| author | Jyotsna Chawla Ilana Goldowitz Jenna Oberstaller Min Zhang Camilla Valente Pires Francesca Navarro Lauriane Sollelis Chengqi C. Q. Wang Andreas Seyfang Jeffrey Dvorin Thomas D. Otto Julian C. Rayner Matthias Marti John H. Adams |
| author_facet | Jyotsna Chawla Ilana Goldowitz Jenna Oberstaller Min Zhang Camilla Valente Pires Francesca Navarro Lauriane Sollelis Chengqi C. Q. Wang Andreas Seyfang Jeffrey Dvorin Thomas D. Otto Julian C. Rayner Matthias Marti John H. Adams |
| author_sort | Jyotsna Chawla |
| collection | DOAJ |
| description | ABSTRACT Transmission of the deadly malaria parasite Plasmodium falciparum from humans to mosquitoes is achieved by specialized intraerythrocytic sexual forms called gametocytes. Though the crucial regulatory mechanisms leading to gametocyte commitment have recently come to light, networks of genes that control sexual development remain to be elucidated. Here, we report a pooled-mutant screen to identify genes associated with gametocyte development in P. falciparum. Our results categorized genes that modulate gametocyte progression as hypoproducers or hyperproducers of gametocytes, and the in-depth analysis of individual clones confirmed phenotypes in sexual commitment rates and putative functions in gametocyte development. We present a new set of genes that have not been implicated in gametocytogenesis before and demonstrate the potential of forward genetic screens in isolating genes impacting parasite sexual biology, an exciting step toward the discovery of new antimalarials for a globally significant pathogen. IMPORTANCE Blocking human-to-vector transmission is an essential step toward malaria elimination. Gametocytes are solely responsible for achieving this transmission and represent an opportunity for therapeutic intervention. While these falciform-shaped parasite stages were first discovered in the 1880s, our understanding of the genetic determinants responsible for their formation and molecular mechanisms that drive their development is limited. In this work, we developed a scalable screening methodology with piggyBac mutants to identify genes that influence the development of gametocytes in the most lethal human malaria parasite, P. falciparum. By doing so, we lay the foundation for large-scale functional genomic studies specifically designed to address remaining questions about sexual commitment, maturation, and mosquito infection in P. falciparum. Such functional genetic screens will serve to expedite the identification of essential pathways and processes for the development of novel transmission-blocking agents. |
| first_indexed | 2024-03-13T05:21:47Z |
| format | Article |
| id | doaj.art-ebea4ef831464fd79e290f35aa33e43a |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-13T05:21:47Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-ebea4ef831464fd79e290f35aa33e43a2023-06-15T13:18:30ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-06-0111310.1128/spectrum.04164-22Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparumJyotsna Chawla0Ilana Goldowitz1Jenna Oberstaller2Min Zhang3Camilla Valente Pires4Francesca Navarro5Lauriane Sollelis6Chengqi C. Q. Wang7Andreas Seyfang8Jeffrey Dvorin9Thomas D. Otto10Julian C. Rayner11Matthias Marti12John H. Adams13Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USADepartment of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USACenter for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USACenter for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USACenter for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USABoston Children’s Hospital and Harvard Medical School, Harvard Medical School, Boston, Massachusetts, USAInstitute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United KingdomCenter for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USABoston Children’s Hospital and Harvard Medical School, Harvard Medical School, Boston, Massachusetts, USAInstitute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United KingdomCambridge Institute for Medical Research, University of Cambridge, Cambridge, United KingdomDepartment of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USADepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USAABSTRACT Transmission of the deadly malaria parasite Plasmodium falciparum from humans to mosquitoes is achieved by specialized intraerythrocytic sexual forms called gametocytes. Though the crucial regulatory mechanisms leading to gametocyte commitment have recently come to light, networks of genes that control sexual development remain to be elucidated. Here, we report a pooled-mutant screen to identify genes associated with gametocyte development in P. falciparum. Our results categorized genes that modulate gametocyte progression as hypoproducers or hyperproducers of gametocytes, and the in-depth analysis of individual clones confirmed phenotypes in sexual commitment rates and putative functions in gametocyte development. We present a new set of genes that have not been implicated in gametocytogenesis before and demonstrate the potential of forward genetic screens in isolating genes impacting parasite sexual biology, an exciting step toward the discovery of new antimalarials for a globally significant pathogen. IMPORTANCE Blocking human-to-vector transmission is an essential step toward malaria elimination. Gametocytes are solely responsible for achieving this transmission and represent an opportunity for therapeutic intervention. While these falciform-shaped parasite stages were first discovered in the 1880s, our understanding of the genetic determinants responsible for their formation and molecular mechanisms that drive their development is limited. In this work, we developed a scalable screening methodology with piggyBac mutants to identify genes that influence the development of gametocytes in the most lethal human malaria parasite, P. falciparum. By doing so, we lay the foundation for large-scale functional genomic studies specifically designed to address remaining questions about sexual commitment, maturation, and mosquito infection in P. falciparum. Such functional genetic screens will serve to expedite the identification of essential pathways and processes for the development of novel transmission-blocking agents.https://journals.asm.org/doi/10.1128/spectrum.04164-22functional genomicspiggyBacinsertional mutagenesisgametocytogenesissexual development |
| spellingShingle | Jyotsna Chawla Ilana Goldowitz Jenna Oberstaller Min Zhang Camilla Valente Pires Francesca Navarro Lauriane Sollelis Chengqi C. Q. Wang Andreas Seyfang Jeffrey Dvorin Thomas D. Otto Julian C. Rayner Matthias Marti John H. Adams Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum Microbiology Spectrum functional genomics piggyBac insertional mutagenesis gametocytogenesis sexual development |
| title | Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum |
| title_full | Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum |
| title_fullStr | Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum |
| title_full_unstemmed | Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum |
| title_short | Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum |
| title_sort | phenotypic screens identify genetic factors associated with gametocyte development in the human malaria parasite plasmodium falciparum |
| topic | functional genomics piggyBac insertional mutagenesis gametocytogenesis sexual development |
| url | https://journals.asm.org/doi/10.1128/spectrum.04164-22 |
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