ORCID Profile
0000-0002-1806-8260
Current Organisation
Houston Methodist Research Institute
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Publisher: Springer Science and Business Media LLC
Date: 13-11-2018
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2021
Abstract: Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences h er annotation, experimental design, and interpretation. We have generated a new C. parvum IOWA genome assembly supported by Pacific Biosciences (PacBio) and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species: C. parvum , Cryptosporidium hominis , and Cryptosporidium tyzzeri . We made 1926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns, and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum , C. hominis , and C. tyzzeri revealed that most “missing” orthologs are found, suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation, and single-nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free, and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.
Publisher: Cold Spring Harbor Laboratory
Date: 29-01-2020
DOI: 10.1101/2021.01.29.428682
Abstract: Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community still relies on a fragmented reference genome sequence from 2004. Incomplete reference sequences h er experimental design and interpretation. We have generated a new C. parvum IOWA genome assembly supported by PacBio and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species C. parvum , C. hominis and C. tyzzeri . The new C. parvum IOWA reference genome assembly is larger, gap free and lacks ambiguous bases. This chromosomal assembly recovers 13 of 16 possible telomeres and raises a new hypothesis for the remaining telomeres and associated subtelomeric regions. Comparative annotation revealed that most “missing” orthologs are found suggesting that species differences result primarily from structural rearrangements, gene copy number variation and SNVs in C. parvum, C. hominis and C. tyzzeri . We made ,500 C. parvu m annotation updates based on experimental evidence. They included new transporters, ncRNAs, introns and altered gene structures. The new assembly and annotation revealed a complete DNA methylase Dnmt2 ortholog. 190 genes under positive selection including many new candidates were identified using the new assembly and annotation as reference. Finally, possible subtelomeric lification and variation events in C. parvum are detected that reveal a new level of genome plasticity that will both inform and impact future research.
Publisher: Cold Spring Harbor Laboratory
Date: 15-05-2020
DOI: 10.1101/2020.05.13.093591
Abstract: Malaria remains a major global health problem, and there exists a constant need to identify druggable weaknesses in P. falciparum biology. The endoplasmic reticulum (ER) has many essential roles in the asexual lifecycle and may offer new drug targets, but it remains critically understudied. We generated conditional mutants of the putative redox-active, ER chaperone Pf J2, and show that it is essential for parasite survival. Using a redox-active cysteine crosslinker, we identify its substrates to be other mediators of oxidative folding, Pf PDI8 and Pf PDI11, suggesting a redox-regulatory role for Pf J2. Knockdown of these protein disulfide isomerases in Pf J2 conditional mutants show that Pf PDI11 is not essential, while Pf PDI8 is essential for asexual growth and may work in a complex with PfJ2 and other ER chaperones. Finally, we show that these redox interactions in the parasite ER are sensitive to small molecule inhibition. Together these data build a model for how oxidative folding occurs in the P. falciparum ER and demonstrate its suitability for antimalarial drug development.
Publisher: Public Library of Science (PLoS)
Date: 03-02-2021
DOI: 10.1371/JOURNAL.PPAT.1009293
Abstract: Malaria remains a major global health problem, creating a constant need for research to identify druggable weaknesses in P . falciparum biology. As important components of cellular redox biology, members of the Thioredoxin (Trx) superfamily of proteins have received interest as potential drug targets in Apicomplexans. However, the function and essentiality of endoplasmic reticulum (ER)-localized Trx-domain proteins within P . falciparum has not been investigated. We generated conditional mutants of the protein Pf J2—an ER chaperone and member of the Trx superfamily—and show that it is essential for asexual parasite survival. Using a crosslinker specific for redox-active cysteines, we identified Pf J2 substrates as Pf PDI8 and Pf PDI11, both members of the Trx superfamily as well, which suggests a redox-regulatory role for Pf J2. Knockdown of these PDIs in Pf J2 conditional mutants show that Pf PDI11 may not be essential. However, Pf PDI8 is required for asexual growth and our data suggest it may work in a complex with Pf J2 and other ER chaperones. Finally, we show that the redox interactions between these Trx-domain proteins in the parasite ER and their substrates are sensitive to small molecule inhibition. Together these data build a model for how Trx-domain proteins in the P . falciparum ER work together to assist protein folding and demonstrate the suitability of ER-localized Trx-domain proteins for antimalarial drug development.
Location: United States of America
No related grants have been discovered for Rodrigo de Paula Baptista.