PlasmoSEP: Predicting surface-exposed proteins on the malaria parasite using semisupervised self-training and expert-annotated data

EL-Manzalawy, Yasser; Munoz, Elyse E.; Lindner, Scott E.; Honavar, Vasant

doi:10.1002/pmic.201600249

Cited by 17 publications

(10 citation statements)

References 40 publications

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“…falciparum [ 20 ] or P . yoelii [ 74 ] salivary gland sporozoites. Several of these are known to be secreted and/or surface-exposed on sporozoites, including CSP, TRAP, SPELD [ 70 ], GEST, sporozoite surface protein 3 (SSP3; PVP01_1427900), hexose transporter (HT; PVP01_0420400) and CelTOS.…”

Section: Resultsmentioning

confidence: 99%

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Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites

et al. 2017

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Plasmodium falciparum and Plasmodium vivax cause the majority of human malaria cases. Research efforts predominantly focus on P. falciparum because of the clinical severity of infection and associated mortality rates. However, P. vivax malaria affects more people in a wider global range. Furthermore, unlike P. falciparum, P. vivax can persist in the liver as dormant hypnozoites that can be activated weeks to years after primary infection, causing relapse of symptomatic blood stages. This feature makes P. vivax unique and difficult to eliminate with the standard tools of vector control and treatment of symptomatic blood stage infection with antimalarial drugs. Infection by Plasmodium is initiated by the mosquito-transmitted sporozoite stage, a highly motile invasive cell that targets hepatocytes in the liver. The most advanced malaria vaccine for P. falciparum (RTS,S, a subunit vaccine containing of a portion of the major sporozoite surface protein) conferred limited protection in Phase III trials, falling short of WHO-established vaccine efficacy goals. However, blocking the sporozoite stage of infection in P. vivax, before the establishment of the chronic liver infection, might be an effective malaria vaccine strategy to reduce the occurrence of relapsing blood stages. It is also thought that a multivalent vaccine comprising multiple sporozoite surface antigens will provide better protection, but a comprehensive analysis of proteins in P. vivax sporozoites is not available. To inform sporozoite-based vaccine development, we employed mass spectrometry-based proteomics to identify nearly 2,000 proteins present in P. vivax salivary gland sporozoites. Analysis of protein post-translational modifications revealed extensive phosphorylation of glideosome proteins as well as regulators of transcription and translation. Additionally, the sporozoite surface proteins CSP and TRAP, which were recently discovered to be glycosylated in P. falciparum salivary gland sporozoites, were also observed to be similarly modified in P. vivax sporozoites. Quantitative comparison of the P. vivax and P. falciparum salivary gland sporozoite proteomes revealed a high degree of similarity in protein expression levels, including among invasion-related proteins. Nevertheless, orthologs with significantly different expression levels between the two species could be identified, as well as highly abundant, species-specific proteins with no known orthologs. Finally, we employed chemical labeling of live sporozoites to isolate and identify 36 proteins that are putatively surface-exposed on P. vivax salivary gland sporozoites. In addition to identifying conserved sporozoite surface proteins identified by similar analyses of other Plasmodium species, our analysis identified several as-yet uncharacterized proteins, including a putative 6-Cys protein with no known ortholog in P. falciparum.

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Section: Resultsmentioning

confidence: 99%

“… (e) Evidence for the protein being surface exposed in P . yoelii salivary gland sporozoites [ 74 ]. “Detected” indicates the protein was detected in either of two biological replicates.…”

Section: Resultsmentioning

confidence: 99%

Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites

et al. 2017

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“…Moreover, it allowed the identification and validation of the putative surface proteome of sporozoites, and serendipitously revealed prominent post‐translational modifications of key vaccine antigens (CSP, TRAP) that may affect vaccine efficacy (Harupa et al ., ; Swearingen et al ., ). These proteomic studies, now conducted across multiple Plasmodium species, have allowed us to define parameters that are predictive of the surface exposure status of Plasmodium proteins (El‐Manzalawy et al ., ). Together, these experiments have paved the way to finally achieve targeted proteomics of the sporozoite stage, and to allow a comparison of critical regulatory complexes across transmission stages of the parasite.…”

Section: Introductionmentioning

confidence: 97%

ALBA4 modulates its stage‐specific interactions and specific mRNA fates during Plasmodium yoelii growth and transmission

Munoz

Hart

Walker

et al. 2017

Molecular Microbiology

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Summary Transmission of the malaria parasite occurs in an unpredictable moment, when a mosquito takes a blood meal. Plasmodium has therefore evolved strategies to prepare for transmission, including translationally repressing and protecting mRNAs needed to establish the infection. However, mechanisms underlying these critical controls are not well understood, including whether Plasmodium changes its translationally repressive complexes and mRNA targets in different stages. Efforts to understand this have been stymied by severe technical limitations due to substantial mosquito contamination of samples. Here using P. yoelii, for the first time we provide a proteomic comparison of a protein complex across asexual blood, sexual, and sporozoite stages, along with a transcriptomic comparison of the mRNAs that are affected in these stages. We find that the Apicomplexan-specific ALBA4 RNA-binding protein acts to regulate development of the parasite’s transmission stages, and that ALBA4 associates with both stage-specific and stage-independent partners to produce opposing mRNA fates. These efforts expand our understanding and ability to interrogate both sexual and sporozoite transmission stages and the molecular preparations they evolved to perpetuate their infectious cycle.

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“…In response to this, we have developed a scalable, discontinuous density gradient purification approach for sporozoites that greatly reduces contamination from the mosquito and its microbes 25 . The resulting fully infectious sporozoites have allowed extensive ChIP, transcriptomic (RNA-seq) and proteomic (nanoLC-MS/MS) analyses of sporozoites from both rodent-infectious ( P. yoelii ) and human-infectious ( P. falciparum , P. vivax ) parasites 26–32 . Taken together, these studies demonstrate that ‘omics’ level efforts on sporozoites are now experimentally practical, and thus reopen long standing questions of mechanisms underlying critical sporozoite functions.…”

Section: Introductionmentioning

confidence: 99%

Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

Lindner

Swearingen

Shears

et al. 2019

Preprint

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22 Introduction: 41Malaria remains one of the great global health problems today, taking a large toll on people in the 42 tropics and subtropics. This disease, caused by Plasmodium parasites, affects over 200 million people 43 annually and kills over 400,000 (WHO World Malaria Report 2018). While a protein-based subunit 44 vaccine (RTS,S) has recently been licensed and is being used for pilot implementation in three Saharan African countries, its protection has been limited and relatively short-lived in clinical trials 1 . 46 Identifying and fully testing an effective and long-lasting malaria vaccine remains a chief goal that has 47 yet to be achieved. Accomplishing this will require greater knowledge of the basic biology of the pre-48 erythrocytic sporozoite and liver stage parasites. Promising new whole-parasite vaccine candidates, 49 based upon the sporozoite form of the parasite, are on the horizon and hopefully will meet these needs 50 2 . 51Plasmodium parasites are transmitted between hosts by an infected female Anopheles mosquito 52 (reviewed in 3 ). Following uptake of male and female gametocytes by the mosquito during a blood meal 53 of an infected host, these parasites activate into male and female gametes in the midgut, fuse into a 54 zygote, and develop into a motile ookinete, which burrows through the midgut wall and establishes an 55 oocyst under the basal lamina. Within the oocyst, the parasite undergoes sporogony to produce up to 56 five thousand oocyst sporozoites 4 . These oocyst sporozoites are weakly infectious if injected directly 57 into a naïve mammalian host 5 , but become highly infectious following proteolytic rupture of the oocyst 58 wall and transit through the mosquito hemocoel. Sporozoites further gain infectivity after invasion of 59 the salivary glands 5,6 . Interestingly, the gain of infectivity for the mammalian host is concomitant with a 60 loss of infectivity for the salivary glands. Within the glands, the sporozoites await transmission as 61 salivary gland sporozoites, which occurs when the mosquito takes its next blood meal. Infection of a 62 host begins with the injection of salivary gland sporozoites into the skin. Following this, sporozoites exit 63 the bite site in the skin, locate and enter the vasculature, and passively travel to the liver, where 64 sporozoites can productively infect hepatocytes, which initiates the life cycle progression in the 65 mammalian host 7 . Moreover, because relatively few sporozoites are injected during a mosquito bite 8 , 66 this transmission event bottleneck has been the focus of intervention efforts using drugs, subunit 67 vaccines, and attenuated whole parasite vaccines 2 . 68Fundamental studies of sporozoite biology have informed efforts to inhibit and/or arrest the parasite 69 during development. To date, genetically-attenuated parasite (GAP) vaccine candidates were generated 70 by the deletion of genes whose transcripts are Up-regulated in Infective (Salivary Gland) Sporozoites 71 (UIS). The UIS gene family was originally determi...

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PlasmoSEP: Predicting surface-exposed proteins on the malaria parasite using semisupervised self-training and expert-annotated data

Cited by 17 publications

References 40 publications

Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites

Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites

ALBA4 modulates its stage‐specific interactions and specific mRNA fates during Plasmodium yoelii growth and transmission

Extensive Transcriptional and Translational Regulation Occur During the Maturation of Malaria Parasite Sporozoites

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