Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice DOI Creative Commons

Brandon K. Sack,

Sebastian A. Mikolajczak,

Matthew Fishbaugher

и другие.

npj Vaccines, Год журнала: 2017, Номер 2(1)

Опубликована: Окт. 4, 2017

A malaria vaccine that prevents infection will be an important new tool in continued efforts of elimination, and such vaccines are under intense development for the major human parasite Plasmodium falciparum (Pf). Antibodies elicited by can block initial phases when sporozoites deposited into skin mosquito bite then target liver further development. However, there currently no standardized vivo preclinical models measure inhibitory activity antibody specificities against Pf sporozoite via bite. Here, we use liver-chimeric mice as a challenge model to assess prevention natural antibodies. We demonstrate these consistently infected with this combined passive transfer either monoclonal antibodies or polyclonal IgG from immune serum antibody-mediated blocking using bioluminescent imaging. This methodology is useful down-select functional investigate mechanisms correlates protection clinical trials, thereby informing rational optimization.

Язык: Английский

Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites DOI Creative Commons
Kristian E. Swearingen, Scott E. Lindner, Erika L. Flannery

и другие.

PLoS neglected tropical diseases, Год журнала: 2017, Номер 11(7), С. e0005791 - e0005791

Опубликована: Июль 31, 2017

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

Язык: Английский

Процитировано

86
Plasmodium P36 determines host cell receptor usage during sporozoite invasion DOI Creative Commons

Giulia Manzoni,

Carine Marinach,

Selma Topçu

и другие.

eLife, Год журнала: 2017, Номер 6

Опубликована: Май 16, 2017

Plasmodium sporozoites, the mosquito-transmitted forms of malaria parasite, first infect liver for an initial round replication before emergence pathogenic blood stages. Sporozoites represent attractive targets antimalarial preventive strategies, yet mechanisms parasite entry into hepatocytes remain poorly understood. Here we show that two main species causing in humans, falciparum and vivax, rely on distinct host cell surface proteins, CD81 Scavenger Receptor BI (SR-BI), respectively, to hepatocytes. By contrast, SR-BI fulfil redundant functions during infection by rodent P. berghei. Genetic analysis sporozoite factors reveals 6-cysteine domain protein P36 as a major determinant receptor usage. Our data provide molecular insights invasion pathways used different parasites hepatocytes, establish functional link between putative ligand receptors.

Язык: Английский

Процитировано

82
Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages DOI Creative Commons
Yevel Flores-García,

Sonia M. Herrera,

Hugo Jhun

и другие.

Malaria Journal, Год журнала: 2019, Номер 18(1)

Опубликована: Дек. 1, 2019

The circumsporozoite protein (CSP) of Plasmodium is a key surface antigen that induces antibodies and T-cells, conferring immune protection in animal models humans. However, much the work on CSP immunity has been developed based studies using rodent or non-human primate antigens, which may not be entirely translatable to expressed by human malaria parasites, especially considering host specificity different species.Using genetically engineered strain berghei expresses luciferase, GFP falciparum orthologue CSP, effect laboratory preparation, mosquito treatment mouse factors sporozoite infectivity was assessed an vivo bioluminescence assay mice. This compared with PCR-based already described monoclonal antibody can provide sterile against challenge.Bioluminescence demonstrated similar detection levels quantity kinetics liver-stage infection, detection. used evaluate delivery method infectivity, as well effects age, sex Finally, this test protective capacity AB317; results strongly recapitulate findings previous antibody.The PbGFP-Luc line imaging highly sensitive read-outs infection mice, useful reliably potency pre-erythrocytic interventions.

Язык: Английский

Процитировано

71
Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts DOI Creative Commons

Sash Lopaticki,

Annie Yang, Alan John

и другие.

Nature Communications, Год журнала: 2017, Номер 8(1)

Опубликована: Сен. 11, 2017

Abstract O-glycosylation of the Plasmodium sporozoite surface proteins CSP and TRAP was recently identified, but role this modification in parasite life cycle its relevance to vaccine design remain unclear. Here, we identify protein O-fucosyltransferase (POFUT2) responsible for O-glycosylating TRAP. Genetic disruption POFUT2 falciparum results ookinetes that are attenuated colonizing mosquito midgut, an essential step malaria transmission. Some POFUT2-deficient parasites mature into salivary gland sporozoites although they impaired gliding motility, cell traversal, hepatocyte invasion, production exoerythrocytic forms humanized chimeric liver mice. These defects can be attributed destabilization incorrect trafficking bearing thrombospondin repeats (TSRs). Therefore, plays a similar metazoans: it ensures TSR as part non-canonical glycosylation-dependent endoplasmic reticulum quality control mechanism.

Язык: Английский

Процитировано

66
Structural delineation of potent transmission-blocking epitope I on malaria antigen Pfs48/45 DOI Creative Commons
Prasun Kundu,

Anthony Semesi,

Matthijs M. Jore

и другие.

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Окт. 22, 2018

Interventions that can block the transmission of malaria-causing Plasmodium falciparum (Pf) between human host and Anopheles vector have potential to reduce incidence malaria. Pfs48/45 is a gametocyte surface protein critical for parasite development transmission, its targeting by monoclonal antibody (mAb) 85RF45.1 leads potent reduction transmission. Here, we reveal how 6C domain adopts (SAG1)-related-sequence (SRS) fold. We structurally delineate epitope I show mAb recognizes an electronegative with nanomolar affinity. Analysis sequences reveals polymorphisms are rare residues involved at binding interface. Humanization rat-derived conserved mode recognition activity parental antibody, while also improving thermostability. Our work has implications transmission-blocking interventions, both through vaccine designs testing passive delivery mAbs in humans.

Язык: Английский

Процитировано

64
CRISPR/Cas9 and glycomics tools for Toxoplasma glycobiology DOI Creative Commons
Elisabet Gas‐Pascual,

H. Travis Ichikawa,

M. Osman Sheikh

и другие.

Journal of Biological Chemistry, Год журнала: 2018, Номер 294(4), С. 1104 - 1125

Опубликована: Ноя. 22, 2018

Язык: Английский

Процитировано

63
Glycosylation in malaria parasites: what do we know? DOI
D. Channe Gowda, Louis H. Miller

Trends in Parasitology, Год журнала: 2024, Номер 40(2), С. 131 - 146

Опубликована: Янв. 22, 2024

Язык: Английский

Процитировано

7
iDC-targeting PfCSP mRNA vaccine confers superior protection against Plasmodium compared to conventional mRNA DOI Creative Commons

Sean Yanik,

Varsha Venkatesh,

James T. Gordy

и другие.

npj Vaccines, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 19, 2025

Malaria resurgence in 2022 saw 249 million clinical cases and 608,000 deaths, mostly children under five. The WHO-approved circumsporozoite protein (CSP)-targeting vaccines, RTS,S R21, remain limited availability. Strong humoral responses are crucial for sporozoite neutralization before hepatocyte infection, yet first-generation vaccines provide suboptimal protection, necessitating improved strategies. With the success of mRNA-LNP against COVID-19, there is interest leveraging this approach to malaria. Here, we developed a novel chemokine fusion mRNA vaccine targeting immature dendritic cells (iDC) enhance immunity P. falciparum CSP (PfCSP). Mice immunized with MIP3α-CSP exhibited stronger CD4 + T cell higher anti-NANP6 antibody titers than conventional mRNA-LNP. Importantly, upon berghei PfCSP transgenic challenge, provided significantly greater protection from liver strongly associated multifunctional titers. This study underscores iDC as promising strategy malaria efficacy.

Язык: Английский

Процитировано

1
Bioinformatic discovery of type 11 secretion system (T11SS) cargo across the Proteobacteria DOI Creative Commons
Alex S. Grossman, Nicholas C. Mucci, Sarah Kauffman

и другие.

Microbial Genomics, Год журнала: 2025, Номер 11(5)

Опубликована: Май 21, 2025

Graphical Abstract

Язык: Английский

Процитировано

1
A Putative Small Solute Transporter Is Responsible for the Secretion of G377 and TRAP-Containing Secretory Vesicles during Plasmodium Gamete Egress and Sporozoite Motility DOI Creative Commons
Jessica Kehrer, Mirko Singer, Leandro Lemgruber

и другие.

PLoS Pathogens, Год журнала: 2016, Номер 12(7), С. e1005734 - e1005734

Опубликована: Июль 18, 2016

Regulated protein secretion is required for malaria parasite life cycle progression and transmission between the mammalian host mosquito vector. During from to vector, exocytosis of highly specialised secretory vesicles, such as osmiophilic bodies, key dissolution red blood cell parasitophorous vacuole membranes enabling gamete egress. The positioning adhesins TRAP family, micronemes sporozoite surface, essential gliding motility host. Here we identify a conserved role putative pantothenate transporter PAT in Plasmodium berghei vesicle fusion two distinct classes vesicles gametocytes sporozoites. membrane component bodies Despite normal formation trafficking surface upon activation, PAT-deficient gametes fail discharge their contents, remain intraerythrocytic unavailable fertilisation further development mosquito. Sporozoites lacking secrete TRAP, are immotile thus unable infect subsequent rodent Thus, P. appears regulate populations different forms rather than acting pantothenic during transmission.

Язык: Английский

Процитировано

57