Fidel Zavala

Johns Hopkins University

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Ruth S. Nussenzweig

New York University

Yevel Flores-García

Johns Hopkins University

Ian A. Cockburn

Australian National University

Moriya Tsuji

Columbia University Irving Medical Center

Victor Nussenzweig

New York University

C. Richter King

Program for Appropriate Technology in Health

Diego A. Espinosa

University of California, Berkeley

Emily Locke

Program for Appropriate Technology in Health

Julius Clemence R. Hafalla

London School of Hygiene & Tropical Medicine

Alexandre Morrot

Universidade Federal do Rio de Janeiro

Cooperative Institutions

Johns Hopkins University

124

National Institutes of Health

116

National Institute of Allergy and Infectious Diseases

101

New York University

Harvard University

Johns Hopkins Medicine

University of Washington

Scripps Research Institute

Columbia University Irving Medical Center

Massachusetts General Hospital

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Field observations on the use of anti-sporozoite monoclonal antibodies for determination of infection rates in malaria vectors.

PubMed (1986)

Fabio Esposito Stefania Lombardi Touré Yt Fidel Zavala M. Cóluzzi

Samples of indoor-resting Anopheles gambiae s.1. from Mali and Burkina Faso (West Africa) were processed in order to compare Plasmodium falciparum sporozoite rates obtained by immunoradiometric assay (IRMA) with circumsporozoite (CS) monoclonal antibody and by microscope examination of salivary glands. The immunological method provided sporozoite rates always higher than those obtained by microscope examination. This result does not appear to be related to cross-reactions involving non-sporozoite antigens. A small fraction of IRMA-positive mosquitoes is necessarily negative by microscope, since these mosquitoes actually contain the CS antigen only in the abdomen, presumably in connection with the presence of fully mature oocysts. However, the frequency of these mosquitoes cannot explain in itself an average ratio of 1:2 between microscope and IRMA sporozoite rates. A more important source of difference appears to depend on the detection of positive mosquitoes with low sporozoite numbers which remain more frequently undetected by microscope examination. Failure of salivary gland penetration by sporozoites is also considered as a possible source of discrepancy between the two methods.

Immunoradiometric assay

Anopheles gambiae

Circumsporozoite protein

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Citations (10)

Regulation of the CD8+ T cell responses against Plasmodium liver stages in mice

International Journal for Parasitology (2004)

Alexandre Morrot Fidel Zavala

Priming (agriculture)

10.1016/j.ijpara.2004.10.001

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Citations (17)

Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes.

The Journal of Experimental Medicine (1983)

Fidel Zavala Alan H. Cochrane Elizabeth Nardin Ruth S. Nussenzweig Victor Nussenzweig

We have used panels of monoclonal antibodies to circumsporozoite (CS) proteins of Plasmodium falciparium, P. vivax, and P. knowlesi to determine the number of topographically independent epitopes of these antigens. The results of competition binding assays indicated that single regions of the CS molecules were recognized by the homologous monoclonal antibodies. Competition binding assays were also used to study the specificity of antibodies contained in the sera of humans and monkeys that had developed sterile immunity after immunization with irradiated, intact sporozoites. We found that single monoclonal antibodies inhibited 70-95% of the specific binding of the polyclonal antibodies to crude extracts of sporozoites. It appears, therefore, that CS proteins are among the most immunogenic constituents of sporozoites, and that a single region of these molecules contains most of the immunogenic activity. An additional finding was that the immunodominant region of CS molecules is multivalent with regard to the expression of a single epitope. This was demonstrated by the ability of monomers of CS proteins to bind simultaneously two or more molecules of the same monoclonal antibody.

Circumsporozoite protein

Polyclonal antibodies

Plasmodium knowlesi

Antigenicity

10.1084/jem.157.6.1947

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Citations (316)

Expression of the Plasmodium knowlesi circumsporozoite antigen in Escherichia coli directed by Plasmodium bacterial-like promoter sequences

Gene (1986)

Ariel Ruiz i Altaba Luiz S. Ozaki Fidel Zavala G. Nigel Godson

Plasmodium knowlesi

10.1016/0378-1119(86)90092-2

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Citations (4)

Immune response to glutaraldehyde-treated cells. I. Dissociation of immunological memory and antibody production.

PubMed (1979)

Alicia Ramos Fidel Zavala G Hoecker

Glutaraldehyde (GA)-treated sheep red blood cells (SRBC) or H-2-allogeneic spleen cells (SC), induced immunological memory with absent or markedly reduced primary antibody production. In contrast, a normal secondary response was obtained when GA-SRBC or GA-SC were given to mice primed with the corresponding untreated antigens. The secondary response of mice primed and boosted with GA-treated cells was relatively high with GA-SRBC, and negative or very low with GA-SC. Morphological studies of the fate of intraperitoneally injected cells showed that endocytosed GA-SRBC persisted much longer in peritoneal macrophages than untreated SRBC. Simultaneous challenge of mice with untreated and GA-treated SRBC revealed that phagocytosis and digestion of both types of cells in the same macrophage proceeded independently of each other. The primary response of mice receiving both SRBC and GA-SRBC was entirely similar to the response when SRBC alone was given.

Glutaraldehyde

Antibody response

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Citations (6)

[Multi-use preparations in dentistry. 1].

PubMed (1986)

P Sarasqueta C Cristóbal Fidel Zavala Molina Moguel Jl

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The practical aspect of long-distance transmission

Students Quarterly Journal (1939)

Fidel Zavala

10.1049/sqj.1939.0043

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Citations (0)

Dendritic Cells and Hepatocytes Use Distinct Pathways to Process Protective Antigen from Plasmodium in vivo

PLoS Pathogens (2011)

Ian A. Cockburn Sze Wah Tse Andrea J. Radtke P. Srinivasan Yun‐Chi Chen

Malaria-protective CD8+ T cells specific for the circumsporozoite (CS) protein are primed by dendritic cells (DCs) after sporozoite injection by infected mosquitoes. The primed cells then eliminate parasite liver stages after recognizing the CS epitopes presented by hepatocytes. To define the in vivo processing of CS by DCs and hepatocytes, we generated parasites carrying a mutant CS protein containing the H-2Kb epitope SIINFEKL, and evaluated the T cell response using transgenic and mutant mice. We determined that in both DCs and hepatocytes CS epitopes must reach the cytosol and use the TAP transporters to access the ER. Furthermore, we used endosomal mutant (3d) and cytochrome c treated mice to address the role of cross-presentation in the priming and effector phases of the T cell response. We determined that in DCs, CS is cross-presented via endosomes while, conversely, in hepatocytes protein must be secreted directly into the cytosol. This suggests that the main targets of protective CD8+ T cells are parasite proteins exported to the hepatocyte cytosol. Surprisingly, however, secretion of the CS protein into hepatocytes was not dependent upon parasite-export (Pexel/VTS) motifs in this protein. Together, these results indicate that the presentation of epitopes to CD8+ T cells follows distinct pathways in DCs when the immune response is induced and in hepatocytes during the effector phase.

Cross-Presentation

10.1371/journal.ppat.1001318

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Citations (98)

The conformational restriction of synthetic peptides, including a malaria peptide, for use as immunogens

Philosophical transactions of the Royal Society of London. Series B, Biological sciences (1989)

Arnold C. Satterthwait Thomas Arrhenius Robert A. Hagopian Fidel Zavala Victor Nussenzweig

A new strategy is advanced for the conformational restriction of peptidyl immunogens. Our approach is to replace putative amide-amide hydrogen bonds with covalent hydrogen-bond mimics. Because on average every other amino acid in a protein engages in this bond, the syntheses of diversely shaped peptides can be contemplated. Synthetic methods for introducing a potential hydrogen-bond mimic into a peptide with α-helical potential is reported and the structural consequences are discussed. The replacement of the hydrogen bond with a chemical link will modify as well as shape the peptide. To explore the consequences of these changes, a potential synthetic vaccine for malaria, the repeating tetrapeptide Asn-Pro-Asn-Ala, was conformationally restricted. Antibodies to the shaped malarial peptide showed a strong cross reaction with Plasmodium falciparum sporozoites.

Tetrapeptide

Peptide bond

Amide

10.1098/rstb.1989.0036

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Citations (18)

The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites

Nature (2006)

Kota Arun Kumar Gen‐ichiro Sano Silvia Beatriz Boscardin Ruth S. Nussenzweig Michel C. Nussenzweig

Circumsporozoite protein

Infectivity

Plasmodium (life cycle)

10.1038/nature05361

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Citations (250)