ORCID Profile
0000-0003-2954-7547
Current Organisations
Swarthmore College
,
Johns Hopkins Bloomberg School of Public Health
,
Dartmouth Medical School
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-06-2021
DOI: 10.1126/SCITRANSLMED.ABG2344
Abstract: A functional human IgA response to malaria targets a conserved epitope in the N terminus of the Plasmodium falciparum circumsporozoite protein.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-03-2021
Abstract: A better understanding of the molecular mechanisms underlying the development of Plasmodium parasites in Anopheles mosquitoes would facilitate the development of malaria vaccines and of novel strategies to interrupt disease transmission. We characterized, at the single-cell level, the gene expression profiles of sporozoites from the rodent malaria parasite Plasmodium berghei , throughout their development in mosquitoes and upon salivation. Our analyses reveal heterogeneity in gene expression among parasites isolated from the same anatomical location, suggesting that parasite development is asynchronous in mosquitoes. In addition, our results highlight the role of gene expression changes in regulating the ability of sporozoites to remain quiescent in the salivary glands, and their rapid reactivation upon salivation.
Publisher: EMBO
Date: 22-03-2021
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41467-022-33403-9
Abstract: Diverse compounds target the Plasmodium falciparum Na + pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4 G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na + regulation. The G358S mutation reduces the affinity of PfATP4 for Na + and is associated with an increase in the parasite’s resting cytosolic [Na + ]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4 G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.
Publisher: American Society for Microbiology
Date: 20-09-2022
DOI: 10.1128/AAC.00418-22
Abstract: As the malaria parasite becomes resistant to every drug that we develop, the identification and development of novel drug candidates are essential. Many studies have screened compounds designed to target the clinically important blood stages.
Publisher: American Chemical Society (ACS)
Date: 23-07-2019
Publisher: Cold Spring Harbor Laboratory
Date: 20-05-2019
DOI: 10.1101/642298
Abstract: Plasmodium sporozoites are transmitted from an infected mosquito to mammals in which they infect the liver. The infectivity profile of sporozoites changes as they egress from oocysts on the mosquito midgut into the hemocoel, and then invade the salivary glands, where they maintain a poised and infectious state until transmission occurs. Upon transmission, the sporozoite must then navigate the host skin, vasculature, and liver. All of these feats require distinct repertoires of proteins and capabilities that are coordinated in an appropriate temporal manner. Here, we report the comprehensive and dynamic transcriptomes and proteomes of both oocyst sporozoite and salivary gland sporozoite stages in both rodent-infectious Plasmodium yoelii parasites and human-infectious Plasmodium falciparum parasites. These data robustly define mRNAs and proteins that are U pregulated in O ocyst S porozoites (UOS) or U pregulated in Infectious S porozoites (UIS), which include critical gene products for sporozoite functions, as well as many of unknown importance that are similarly regulated. Moreover, we found that Plasmodium uses two overlapping, extensive, and independent programs of translational repression across sporozoite maturation to temporally regulate specific genes necessary to successfully navigate the mosquito vector and mammalian host environments. Finally, gene-specific validation experiments of selected, translationally repressed transcripts in P. yoelii confirmed the interpretations of the global transcriptomic and proteomic datasets. Together, these data indicate that two waves of translational repression are implemented and relieved at different times in sporozoite maturation to promote its successful life cycle progression.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2019
DOI: 10.1038/S41467-019-12936-6
Abstract: Plasmodium sporozoites are transmitted from infected mosquitoes to mammals, and must navigate the host skin and vasculature to infect the liver. This journey requires distinct proteomes. Here, we report the dynamic transcriptomes and proteomes of both oocyst sporozoites and salivary gland sporozoites in both rodent-infectious Plasmodium yoelii parasites and human-infectious Plasmodium falciparum parasites. The data robustly define mRNAs and proteins that are upregulated in oocyst sporozoites (UOS) or upregulated in infectious sporozoites (UIS) within the salivary glands, including many that are essential for sporozoite functions in the vector and host. Moreover, we find that malaria parasites use two overlapping, extensive, and independent programs of translational repression across sporozoite maturation to temporally regulate protein expression. Together with gene-specific validation experiments, these data indicate that two waves of translational repression are implemented and relieved at different times during sporozoite maturation, migration and infection, thus promoting their successful development and vector-to-host transition.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2019
DOI: 10.1038/S41598-019-49348-X
Abstract: Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P . falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P . falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.
Location: No location found
Location: United States of America
No related grants have been discovered for Photini Sinnis.