DOCSLIB.ORG

A T-Cell Response to a Liver-Stage Plasmodium Antigen Is Not Boosted by Repeated Sporozoite Immunizations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A T-Cell Response to a Liver-Stage Plasmodium Antigen Is Not Boosted by Repeated Sporozoite Immunizations A T-cell response to a liver-stage Plasmodium antigen is not boosted by repeated sporozoite immunizations Sean C. Murphya, Arnold Kasb, Brad C. Stoneb, and Michael J. Bevanc,d,1 aDepartment of Laboratory Medicine, University of Washington Medical Center, Seattle, WA 98195; bBenaroya Research Institute, Seattle, WA 98101; and cDepartment of Immunology, and dThe Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 Contributed by Michael J. Bevan, March 1, 2013 (sent for review February 2, 2013) + Development of an antimalarial subunit vaccine inducing protective instead associated with antibodies and CD4 T-cell responses (21). cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way Thus, CSP is an important but currently insufficient target for use for malaria eradication. Experimental immunization with sporozoites as a single-antigen vaccine. Because responses to non-CSP anti- induces this type of protective response, but the extremely large gens can protect in the absence of CSP-specific immunity in mice number of proteins expressed by Plasmodium parasites has so far (11, 22–25), we and others are working to discover novel protective prohibited the identification of sufficient discrete T-cell antigens to antigens to broaden the immune repertoire. develop subunit vaccines that produce sterile immunity. Here, using Single immunization using CPS or late-arresting GAP ap- mice singly immunized with Plasmodium yoelii sporozoites and high- proaches usually provides greater protection than an equivalent throughput screening, we identified a unique CTL response against number of RAS parasites (11, 26). RAS parasites arrest shortly after the parasite ribosomal L3 protein. Unlike CTL responses to the circum- hepatocyte infection, whereas GAPs progress further depending on sporozoite protein (CSP), the population of L3-specific CTLs was not the specific genetic lesion. CPS completes liver-stage development expanded by multiple sporozoite immunizations. CSP is abundant in and progresses to a brief RBC infection halted by drug treatment. the sporozoite itself, whereas L3 expression does not increase until GAP and CPS approaches express a wider array of proteins than the liver stage. The response induced by a single immunization with RAS. Accordingly, late-arresting GAPs were shown to induce more sporozoites reduces the parasite load in the liver so greatly during diverse CTL responses than RAS vaccination in mice (27). Thus, subsequent immunizations that L3-specific responses are only gen- proteins expressed de novo in the liver [e.g., by CPS and some GAPs erated during the primary exposure. Functional L3-specificCTLscan, like 3-oxoacyl-ACP synthase I/II; PY04452 (FabB/F)-deficient IMMUNOLOGY however, be expanded by heterologous prime-boost regimens. Thus, parasites] and in the red blood cell (RBC) stages (e.g., by CPS) have although repeat sporozoite immunization expands responses to pre- received attention as candidate antigens. However, despite efforts formed antigens like CSP that are present in the sporozoite itself, this by several groups, few non-CSP antigens remain confirmed as CTL immunization strategy may not expand CTLs targeting parasite pro- targets and none are reported to be individually protective (28). teins that are synthesized later. Heterologous strategies may be It remains unclear why there is a paucity of protective antigens needed to increase CTL responses across the entire spectrum of Plas- after sporozoite immunization. The lack of targets may reflect modium liver-stage proteins. technical limitations in antigen discovery, antigenic bias due to homologous sporozoite vaccination, lack of late-stage antigen ex- vaccination | epitope pression, and/or CSP immunodominance. Traditionally, pooled synthetic peptides are used in IFN-γ (IFNγ) enzyme-linked im- alaria parasites cause tremendous morbidity and mortality munosorbent spot (ELISPOT) assays to identify T-cell targets (29), Mworldwide. The only vaccine approach known to induce but even with pooling strategies (30), these approaches require sterile protection against challenge relies on whole organism spo- complex, expensive peptide libraries. In lieu of peptides, plasmid- rozoite-stage parasites. This vaccination is experimentally achieved encoded parasite genes can be transfected into antigen-presenting fi in mice and humans by using radiation-attenuated sporozoites cells (APCs) (31), but this approach is low throughput and dif cult (RAS) (1, 2), genetically attenuated parasites (GAPs) (3), or wild- because of the A/T-richness of Plasmodial genes. Instead here, we type (WT) sporozoites with chloroquine prophylaxis (CPS) (4, 5). used a minigene-based high-throughput screen (HTS) for CTLs (32) to study a library of Plasmodium yoelii-derived antigens in These approaches induce protective antibodies and T cells, with fi cytotoxic T lymphocytes (CTLs) particularly important for pro- sporozoite-vaccinated mice. Our approach identi edauniqueCTL tection against experimental sporozoite challenge (6). target antigen that provided surprising insights about CTL Because sporozoites are difficult to manufacture, a multicom- responses in multiply-immunized mice. ponent subunit vaccine that induces protective CTLs is desirable; Results however, protective antigens must be identified first. Because Plasmodia have >5,000 genes, there are many candidates yet few HTS Reveals Greater CTL Diversity Following Different Sporozoite Immunizations. To identify novel malaria vaccine candidates, we bona fide antigens have been described since the identification of developed a HTS approach based on massively parallel synthesis the circumsporozoite protein (CSP) as a critical target more than of thousands of oligonucleotides that encode candidate peptides 24 y ago (7, 8). CSP coats the sporozoite surface, is shed from the (32) (Fig. S1). Liver-stage expressed genes (33) were subjected to motile sporozoite (9), and is transported to the hepatocyte cyto- H2d class I MHC prediction to produce a sequence library plasm (10). CSP is a target of protective class I-dependent CTL (Dataset S1) encoding 1,988 distinct 17-aa peptides (centered on responses (10–12). Depending on the mouse model, CSP can also + a predicted 9-mer peptide) in 199 pools of 10 minigenes each. elicit important CD4 T-cell responses (13, 14) and MHC class II- dependent IgG responses (15). In some systems, large numbers of adoptively transferred CSP-specific T-cell clones or endogenously Author contributions: S.C.M., B.C.S., and M.J.B. designed research; S.C.M., A.K., and B.C.S. generated CTLs can protect mice against sporozoite challenge (8, performed research; S.C.M., A.K., and B.C.S. contributed new reagents/analytic tools; 12, 14, 16, 17). However, it remains unclear whether CSP-specific S.C.M., B.C.S., and M.J.B. analyzed data; and S.C.M., B.C.S., and M.J.B. wrote the paper. CTLs in naïve subjects can be primed to achieve protection with The authors declare no conflict of interest. existing vaccination approaches. In addition, the CSP-based RTS, 1To whom correspondence should be addressed. E-mail: [email protected]. S vaccine in phase 3 human trials does not trigger strong CTL This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. responses (18, 19). The partial protection (20) from RTS,S is 1073/pnas.1303834110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1303834110 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 Pools were transfected into H2d P815 cells and used for ELISPOT and a single peptide from the PY05881 ribosomal protein L3 assays of mouse splenocytes 6 d after immunization. (GYKSGMSHI) predicted to bind H2-Kd generated ELISPOT In general, low frequency T-cell responses were observed for all responses (Fig. 2C). primary immunization regimens. The background in CPS-immu- The P. yoelii L3 ribosomal protein is expressed in liver and nized mice was significantly higher [22.9 ± 20.2 to 25.5 spot-forming RBC stages (33) and is conserved in Plasmodium berghei ANKA units (SFUs), 95% confidence interval (CI)] than for GAP- (4.7 ± (PBANKA_051190), Plasmodium falciparum (PF10_0272), and 4.7 to 9.6 SFU, 95% CI) or RAS-immunized mice (5.6 ± 4.5 to 6.7 Plasmodium vivax (PVX_111330). By ELISPOT, L3-specific SFU, 95% CI) (P < 0.0001, unpaired Student’s t test, 16 wells for cells responded to low nanomolar peptide concentrations, sim- CPS and RAS, 15 wells for GAP), possibly due to natural killer cell ilar to the behavior of CSP-specificcells(Fig.3A). The L3 re- + activation by infected RBCs (iRBCs) (34). CPS spleens were larger sponse was mediated by CD8 T cells because anti-CD8 but not and contained more pigment than normal-appearing spleens of anti-CD4 antibodies blocked the response (Fig. 3B). By H2-Kd GAP- and RAS-immunized mice, likely due to uptake of drug- binding studies using RMA/S lymphoma cells, both L3 and CSP killed iRBCs. After normalization, CPS and GAP triggered the peptides demonstrated low nanomolar-strength MHC-specific d most positive results (each with 27 incompletely overlapping pools) binding to H2-K (L3 Kd = 0.7 nM compared with CSP Kd 1.6 followed by RAS immunization (17 pools) at P < 0.05 (Fig. 1A and nM) (Fig. 3C). The L3-specific ELISPOT response could also be Fig. S2). Most positive responses produced fewer IFNγ spots than blocked by using anti–H2-Kd antibodies (Fig. S3). the CSP control well. Only two pools were positive in all screens in CSP- and L3-specific responses could be detected in liver lym- CPS, GAP, and RAS immunized mice (pools 79 and 171). All phocytes from CPS- and RAS-immunized mice by ELISPOT 6 d immunizations induced strong ELISPOT responses to the column- after immunization (Fig. S4). Because L3 lacks a canonical signal synthesized CSP-encoding control minigene (Fig. 1A and Fig. S2). sequence and may not traffic to the parasitophorous vacuole or Pool 102 also contained the microarray-synthesized minigene hepatocyte cytosol, we tested responses to cross-presented L3 as encoding the SYVPSAEQI peptide of CSP and was positive in well.
Load more

Recommended publications
  • Research Toward Vaccines Against Malaria
    © 1998 Nature Publishing Group http://www.nature.com/naturemedicine REVIEW Louis Miller (National Institute of Allergy and Infectious Diseases) and Stephen Hoffman (Naval Medical Research Institute) review progress toward developing malaria vaccines. They argue that multiple antigens from different stages may be needed to protect the diverse populations at risk, and that an optimal vaccine would Induce Immunity against all stages. Vaccines for African children, In whom the major mortality occurs, must induce immunity against ase,cual blood stages. Research toward vaccines against malaria Malaria is one of the major causes of the only stage of the life cycle that causes disease and death between the Tropic LOUIS H. MILLER1 disease. The stages before the asexual of Cancer and Tropic of Capricorn. & STEPHEN L. HOFFMAN2 blood stage are lumped together and Plasmodium falciparum has an especially called pre-erythrocytic. A small propor­ profound impact on infants and children in sub-Saharan Africa, tion of the asexual blood stages differentiate into sexual stages, where its effect on health is increasing as chloroquine resistance the gametocytes in red cells that infect mosquitoes; vaccines to spreads across the continent. We believe that vaccination the mosquito stages are called transmission-blocking vaccines. against P. falciparum is the intervention with the greatest poten­ The parasites' multistage life cycle and the fact that immune re­ tial to reduce malaria-associated severe morbidity and mortality sponses that recognize one stage often do not affect the next in areas with the most intense transmission and that it may do stage have made vaccine development for malaria more diffi­ so without necessarily preventing blood stage infection.
    [Show full text]
  • Unexpected Fold in the Circumsporozoite Protein Target of Malaria Vaccines
    Unexpected fold in the circumsporozoite protein target of malaria vaccines Michael B. Doud, Adem C. Koksal, Li-Zhi Mi, Gaojie Song, Chafen Lu, and Timothy A. Springer1 Immune Disease Institute, Children’s Hospital Boston and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Contributed by Timothy A. Springer, April 4, 2012 (sent for review March 19, 2012) Circumsporozoite (CS) protein is the major surface component of Plas- The CS structures reveal a unique “αTSR” domain that is modium falciparum sporozoites and is essential for host cell invasion. related to TSR domains yet has unique features (Figs. 1 C and D A vaccine containing tandem repeats, region III, and thrombospondin and 2). Region III forms an integral part of the fold as a unique type-I repeat (TSR) of CS is efficacious in phase III trials but gives only amphipathic α-helix running orthogonally to the classic three- a 35% reduction in severe malaria in the first year postimmunization. stranded TSR homology region. This α1-helix, together with We solved crystal structures showing that region III and TSR fold into a “CS flap” (Fig. 1 C and D), decorates one face of the TSR asingleunit,an“αTSR” domain. The αTSR domain possesses a hydro- β-sheet (Fig. 2A). By packing against the β-sheet, the region III phobic pocket and core, missing in TSR domains. CS binds heparin, but α-helix gives the αTSR domain a hydrophobic core lacking in αTSR does not. Interestingly, polymorphic T-cell epitopes map to spe- TSR domains. A short linker containing a conserved hydro- cialized αTSR regions.
    [Show full text]
  • Professor Salimata Thurston Née Wade
    2010 Winner of AU-ECOWAS Women Scientists Award Life Sciences and Earth Professor Salimata Thurston née Wade Mrs. Salimata Thurston née Wade is a top-notch tenured Professor of Physiology and Human Nutrition at the Faculty of Sciences and Technology of Université Cheikh Anta Diop, Dakar (UCAD). She was Head of Department of Animal Biology of the FST, UCAD from 2004 to 2006 and currently serves as Director of the Nutrition Laboratory and is in charge of doctoral training at the Ecole Doctorale ED-SEV of UCAD. Born in Dakar, at the Médina, on 28 February 1951, Mrs. Wade completed her primary education in Dakar and continued with secondary education at the Lycée Carnot School for Young Girls later known as Lycée John F. Kennedy. She obtained her baccalauréat D with honours in 1972. She continued her education in France at the Université Paris 7 and specialized in Physiology and General Human Biology, with focus on Nutrition. In 1978, she joined INSERM’s prestigious Unit 1 for Research in Nutrition of the Bichat Hospital. Mrs Wade would spend 9 years there in order to carry out research, particularly on biological signs of malnutrition and effects of interplay between malnutrition and infection. In 1986, Mrs Wade defended her Doctoral thesis on the theme “Transthyretin (Prealbumine) and Thymuline (Zn-FTS) in Protein- Energy Malnutrition” at the Université Paris 7. She was awarded High Honours by the jury. She also underwent several internships in various laboratories, such as Dunn Nutrition Laboratory of the Medical Research Council (HNR) o f Cambridge, England in order to specialise in the measurement of energy expenditure in men and the use of stable isotopes in nutrition.
    [Show full text]
  • Based on the Circumsporozoite Protein Protein: a Case Study With
    Adjuvant-like Effect of Vaccinia Virus 14K Protein: A Case Study with Malaria Vaccine Based on the Circumsporozoite Protein This information is current as Aneesh Vijayan, Carmen E. Gómez, Diego A. Espinosa, of September 26, 2021. Alan G. Goodman, Lucas Sanchez-Sampedro, Carlos Oscar S. Sorzano, Fidel Zavala and Mariano Esteban J Immunol published online 21 May 2012 http://www.jimmunol.org/content/early/2012/05/21/jimmun ol.1102492 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/05/21/jimmunol.110249 Material 2.DC1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 21, 2012, doi:10.4049/jimmunol.1102492 The Journal of Immunology Adjuvant-like Effect of Vaccinia Virus 14K Protein: A Case Study with Malaria Vaccine Based on the Circumsporozoite Protein Aneesh Vijayan,* Carmen E. Go´mez,* Diego A.
    [Show full text]
  • Presence of a Circumsporozoite-Like Protein in Micronemes of Blood-Stage Merozoites of Malaria Parasites A.H
    Presence of a circumsporozoite-like protein in micronemes of blood-stage merozoites of malaria parasites A.H. Cochrane,1 S. Uni,2 M. Maracic,' L. di Giovanni,1 M. Aikawa,2 & R.S. Nussenzweig1 We demonstrate for the first time the presence of a circumsporozoite (CS)-like protein in invasive blood stages of malaria parasites. Immunogold electron microscopy using antisporozoite monoclonal antibodies localized these antigens in the micronemes of merozoites. Western immunoblot and two-dimensional gel electrophoresis of mature blood-stage extracts of Plasmodium falciparum, P. berghei, P. cynomolgi, and P. brasilianum identified polypeptides having the same apparent molecular mass and isoelectric points as the corresponding sporozoite (CS) proteins. The CS-like protein of merozoites is present in relatively minor amounts, compared to the CS protein of sporozoites. Mice with long-term P. berghei blood-induced infections develop antibodies which react with sporozoites. Introduction cursors have been demonstrated in the micronemes of Sporozoites are the invasive stage of plasmodia in- sporozoites (7). oculated into the vertebrate host by the bite of An- opheles mosquitos. Their surface membrane is covered Methods and results by the circumsporozoite (CS) protein which arises CS proteins, like the protective response they induce, from higher M, (relative molecular mass) precursors. have been considered to be stage specific (reviewed in All CS proteins contain an immunodominant region 1). In the present study, using antisporozoite mAbs we consisting of a single epitope which is tandemly re- have demonstrated, for the first time, the presence of peated and species specific. Monoclonal antibodies CS-like proteins in the micronemes of blood-stage (mAbs) directed against this repeat region inhibit merozoites of P.
    [Show full text]
  • Apicomplexan Cytoskeleton and Motors: Key Regulators in Morphogenesis, Cell Division, Transport and Motility
    International Journal for Parasitology 39 (2009) 153–162 Contents lists available at ScienceDirect International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara Invited Review Apicomplexan cytoskeleton and motors: Key regulators in morphogenesis, cell division, transport and motility Joana M. Santos a, Maryse Lebrun b, Wassim Daher a, Dominique Soldati a, Jean-Francois Dubremetz b,* a Department of Microbiology and Molecular Medicine, Faculty of Medicine–University of Geneva CMU, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland b UMR CNRS 5235, Bt 24, CC 107 Université de Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 05, France article info abstract Article history: Protozoan parasites of the phylum Apicomplexa undergo a lytic cycle whereby a single zoite produced by Received 30 July 2008 the previous cycle has to encounter a host cell, invade it, multiply to differentiate into a new zoite gen- Received in revised form 13 October 2008 eration and escape to resume a new cycle. At every step of this lytic cycle, the cytoskeleton and/or the Accepted 16 October 2008 gliding motility apparatus play a crucial role and recent results have elucidated aspects of these pro- cesses, especially in terms of the molecular characterization and interaction of the increasing number of partners involved, and the signalling mechanisms implicated. The present review aims to summarize Keywords: the most recent findings in the field. Apicomplexa Ó 2008 Australian Society for Parasitology Inc. Published by Elsevier Ltd.
    [Show full text]
  • Role of Opsonophagocytosis in Immune Protection Against Malaria
    Review Role of Opsonophagocytosis in Immune Protection against Malaria Wolfgang W. Leitner 1, Megan Haraway 2, Tony Pierson 2 and Elke S. Bergmann-Leitner 2,* 1 Basic Immunology Branch, Division of Allergy, Immunology, and Transplantation/National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA; [email protected] 2 Immunology Core/Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; [email protected] (M.H.); [email protected] (T.P.) * Correspondence: [email protected]; Tel.: +1-301-319-9278 Received: 8 May 2020; Accepted: 26 May 2020; Published: 30 May 2020 Abstract: The quest for immune correlates of protection continues to slow vaccine development. Todate, only vaccine-induced antibodies have been confirmed as direct immune correlates of protection against a plethora of pathogens. Vaccine immunologists, however, have learned through extensive characterizations of humoral responses that the quantitative assessment of antibody responses alone often fails to correlate with protective immunity or vaccine efficacy. Despite these limitations, the simple measurement of post-vaccination antibody titers remains the most widely used approaches for vaccine evaluation. Developing and performing functional assays to assess the biological activity of pathogen-specific responses continues to gain momentum; integrating serological assessments with functional data will ultimately result in the identification of mechanisms that contribute to protective immunity and will guide vaccine development. One of these functional readouts is phagocytosis of antigenic material tagged by immune molecules such as antibodies and/or complement components. This review summarizes our current understanding of how phagocytosis contributes to immune defense against pathogens, the pathways involved, and defense mechanisms that pathogens have evolved to deal with the threat of phagocytic removal and destruction of pathogens.
    [Show full text]
  • The Selection of a Hepatocyte Cell Line Susceptible to Plasmodium Falciparum Sporozoite Invasion That Is Associated with Expression of Glypican-3
    fmicb-10-00127 February 27, 2019 Time: 13:2 # 1 ORIGINAL RESEARCH published: 28 February 2019 doi: 10.3389/fmicb.2019.00127 The Selection of a Hepatocyte Cell Line Susceptible to Plasmodium falciparum Sporozoite Invasion That Is Associated With Expression of Glypican-3 Rebecca E. Tweedell1,2, Dingyin Tao2†, Timothy Hamerly1,2†, Tanisha M. Robinson3†, Simon Larsen4, Alexander G. B. Grønning4, Alessandra M. Norris1, Jonas G. King2,5, Henry Chun Hin Law1, Jan Baumbach4,6‡, Elke S. Bergmann-Leitner3‡ and Rhoel R. Dinglasan1,2* 1 Department of Infectious Diseases and Immunology, Emerging Pathogens Institute, University of Florida, Gainesville, FL, Edited by: United States, 2 W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Celio Geraldo Freire-de-Lima, Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States, 3 Malaria Vaccine Universidade Federal do Rio Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States, 4 Computational BioMedicine Lab, de Janeiro, Brazil Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark, 5 Department Reviewed by: of Biochemistry, Molecular Biology, Entomology & Plant Pathology, Mississippi State University, Starkville, MS, United States, Rodrigo Andrés López-Muñoz, 6 Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Southern University of Chile, Chile Munich, Germany Miguel Prudêncio, University of Lisbon, Portugal In vitro studies of liver stage (LS) development of the human malaria parasite *Correspondence: Rhoel R. Dinglasan Plasmodium falciparum are technically challenging; therefore, fundamental questions [email protected]fl.edu about hepatocyte receptors for invasion that can be targeted to prevent infection remain †These authors have contributed unanswered.
    [Show full text]
  • Malaria Liver Stage Parasites Strategies for Immune Evasion and Host Modulation: Implication for Vaccine Design
    Open Access Austin Journal of Vaccines & Immunotherapeutics Mini Review Malaria Liver Stage Parasites Strategies for Immune Evasion and Host Modulation: Implication for Vaccine Design Dabbu Kumar Jaijyan1, Himanshu Singh1 and Agam Prasad Singh1* Abstract Infectious Diseases Laboratory, National Institute of Malaria is a devastating infectious disease caused by protozoan parasite Immunology, India of the genus Plasmodium. When an infected mosquito bites a vertebrate host *Corresponding author: Singh AP, National Institute it leaves a small number of sporozoites under the skin. Sporozoites from the of Immunology, Aruna Asaf Ali Marg, New Delhi-110067, site of bite, end up in lymph node or liver. In the lymph node these parasite India. Tel: (+91-11) 26703707; 26715032; Fax: +91-11- are degraded and act as source of antigen for the immune system. In liver, the 26717104; Email: [email protected] sporozoites invade into a hepatocyte and develop into mature schizonts. Liver stage parasites are able to evade host immune responses as well as modulate Received: July 19, 2014; Accepted: September 30, the various host pathways. Study of Plasmodium liver stage exportome may 2014; Published: October 16, 2014 provide valuable vaccine candidates and those with strong T cell epitope may be inducted into pre erythrocytic stage vaccine pipeline. Hepatocytes process and present foreign antigens on its surface hence some of the Plasmodium exported proteins are also likely presented on its surface similar to circumsporozoite protein. In terms of designing vaccine delivery system and the antigen load in liver, recent advances suggest that one need to deliver antigen in <20% of hepatocytes. Presence of antigen in large population of hepatocytes (>25%) leads to silencing of CTLs, which are no longer effective in killing the pathogens.
    [Show full text]
  • Evaluating Seroprevalence to Circumsporozoite Protein to Estimate Exposure to Three Species of Plasmodium in the Brazilian Amazo
    Pereira et al. Infectious Diseases of Poverty (2018) 7:46 https://doi.org/10.1186/s40249-018-0428-1 RESEARCH ARTICLE Open Access Evaluating seroprevalence to circumsporozoite protein to estimate exposure to three species of Plasmodium in the Brazilian Amazon Virginia Araujo Pereira1, Juan Camilo Sánchez-Arcila1, Mariana Pinheiro Alves Vasconcelos2, Amanda Ribeiro Ferreira1, Lorene de Souza Videira1, Antonio Teva3, Daiana Perce-da-Silva4, Maria Teresa Queiroz Marques5, Luzia Helena de Carvalho6, Dalma Maria Banic4, Luiz Cristóvão Sobrino Pôrto5 and Joseli Oliveira-Ferreira1* Abstract Background: Brazil has seen a great decline in malaria and the country is moving towards elimination. However, for eventual elimination, the control program needs efficient tools in order to monitor malaria exposure and transmission. In this study, we aimed to evaluate whether seroprevalence to the circumsporozoite protein (CSP) is a good tool for monitoring the exposure to and/or evaluating the burden and distribution of Plasmodium species in the Brazilian Amazon. Methods: Cross-sectional surveys were conducted in a rural area of Porto Velho, Rondônia state. Parasite infection was detected by microscopy and polymerase chain reaction. Antibodies to the sporozoite CSP repeats of Plasmodium vivax, P. falciparum,andP. malariae (PvCS, PfCS, and PmCS) were detected using the enzyme-linked immunosorbent assay technique. Human leukocyte antigen (HLA)-DRB1 and DQB1 genes were typed using Luminex® xMAP® technology. Results: The prevalence of immunoglobulin G against P. vivax CSP peptide (62%) was higher than P. falciparum (49%) and P. malariae (46%) CSP peptide. Most of the studied individuals had antibodies to at least one of the three peptides (72%), 34% had antibodies to all three peptides and 28% were non-responders.
    [Show full text]
  • The Role of Rhomboid Proteases and a Oocyst Capsule Protein
    THE ROLE OF RHOMBOID PROTEASES AND A OOCYST CAPSULE PROTEIN IN MALARIA PATHOGENESIS AND PARASITE DEVELOPMENT BY PRAKASH SRINIVASAN Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Prof. Marcelo Jacobs-Lorena Department of Genetics CASE WESTERN RESERVE UNIVERSITY August, 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS Table of Contents 1 List of Tables 2 List of Figures 4 Acknowledgements 5 Abstract 7 CHAPTER 1: Introduction and Research Objectives 9 Introduction 10 Malaria: History and Facts 10 Discovery of Mosquitoes as vectors 10 Malaria: Life Cycle 12 Life cycle in the vertebrate host 12 Life cycle in the mosquito 15 Sporozoite invasion of the liver 29 Study of gene function in parasites 32 Research Objectives 34 CHAPTER 2: Analysis of Plasmodium and Anopheles Transcriptomes during Oocyst Differentiation 37 CHAPTER 3: PbCap380, a novel Plasmodium Oocyst Capsule Protein
    [Show full text]
  • Mechanisms of Escape from Host Immune Defenses by Apicomplexan Parasites
    Iowa State University Capstones, Theses and Creative Components Dissertations Spring 2020 Mechanisms of Escape from Host Immune Defenses by Apicomplexan Parasites Reannan Barlow Follow this and additional works at: https://lib.dr.iastate.edu/creativecomponents Part of the Parasitology Commons Recommended Citation Barlow, Reannan, "Mechanisms of Escape from Host Immune Defenses by Apicomplexan Parasites" (2020). Creative Components. 470. https://lib.dr.iastate.edu/creativecomponents/470 This Creative Component is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Creative Components by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Mechanisms of Escape from Host Immune Defenses by Apicomplexan Parasites Review Article by Reannan Barlow Overview: A successful pathogen manipulates its host from the moment infection occurs. Apicomplexan parasites are no different. Plasmodium spp., the causative agents of malaria, evade the human immune system so well that they kill hundreds of thousands of people per year. Toxoplasma, though not particularly dangerous to a healthy adult, is a widespread pathogen due to how easily it spreads between host and how it modulates host functions (27). This review discusses how Toxoplasma and Plasmodium avoid clearance by host defenses, highlighting their similarities and differences. Background: Malaria: Malaria is an arthropod-borne disease resulting from an infection with a protozoan parasite of the genus Plasmodium belonging to the phylum Apicomplexa (14). This parasite is arguably, one of the deadliest parasites across the globe. According to the World Health Organization, there were roughly 228 million cases of malaria worldwide and 405,000 deaths in 2018 (10).
    [Show full text]