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Pf332-C231- reactive antibodies affect growth and development of intraerythrocytic Plasmodium falciparum parasites
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology. (Kavs Berzins, Malaria Group)
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
(English)Article in journal (Refereed) Submitted
Keyword [en]
Malaria, Pf332-C231, antibodies, growth inhibition
National Category
Infectious Medicine Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-60515OAI: oai:DiVA.org:su-60515DiVA: diva2:435511
Available from: 2011-08-19 Created: 2011-08-18 Last updated: 2011-08-22Bibliographically approved
In thesis
1. Immunological characteristics of recombinant fragments of the Plasmodium falciparum blood-stage antigen Pf332
Open this publication in new window or tab >>Immunological characteristics of recombinant fragments of the Plasmodium falciparum blood-stage antigen Pf332
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Effective malaria vaccine might help improve control strategies against malaria, but the complexity of interactions between the parasite and its hosts poses challenges. The asexual blood stage P. falciparum antigen Pf332 has potentials as one of the proteins in understanding the complex host-parasite interactions. The interest in Pf332 as a target for parasite neutralizing antibodies, evolved from previous studies demonstrating that Pf332-reactive antibodies inhibits parasite growth in vitro. The presence of natural P. falciparum infection also indicated that Pf332 has the ability to induce protective antibodies.

In paper I, we identified and characterized the immunogenicity of a C-terminal region of Pf332. Immunological analyses carried out with this fragment revealed that rabbit anti-C231 antibodies possess parasite in vitro inhibitory capabilities. In paper II, the functional activity of C231 specific antibodies was confirmed with human-affinity purified antibodies, where the antibodies inhibited late stage parasite development, by the presence of abnormal parasites and disintegrated red cell membranes.

Epidemiological data from malaria endemic area of Senegal (Paper III & IV), showed that antibodies were reactive with two different fragments of Pf332 (C231 and DBL). Distribution of anti-C231 antibodies in the IgG subclasses, gave similar levels of IgG2 and IgG3. The levels of anti-C231 antibodies were associated with protection from clinical malaria, but with DBL reactive antibodies IgG3 was associated with protection from clinical malaria.

We hereby conclude that antigen Pf332 contains immunogenic epitopes, and is a potential target for parasite neutralizing antibodies. The Pf332 protein should thus be considered as a candidate antigen for inclusion in a subunit P. falciparum malaria vaccine.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2011. 82 p.
Keyword
Plasmodium falciparum, Pf332, antibodies, immunity, growth inhibition
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-60540 (URN)978-91-7447-347-6 (ISBN)
Public defence
2011-09-22, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 4: Manuscript. Available from: 2011-08-31 Created: 2011-08-19 Last updated: 2011-08-22Bibliographically approved
2. Studies on Plasmodium falciparum asexual blood stage antigens: RAP-2/RSP-2 and Pf332 in focus
Open this publication in new window or tab >>Studies on Plasmodium falciparum asexual blood stage antigens: RAP-2/RSP-2 and Pf332 in focus
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The life cycle of the malaria parasite is very complex and provides a number of potential targets for vaccination. In this thesis, data on two plasmodial asexual blood stage antigens (RAP-2 and Pf332) are presented.

A partial aim of the work presented herein was to investigate the mechanisms responsible for the destruction of erythroid cells in anaemia, and more specifically to define the role of the rhoptry associated protein (RAP)-2 and other members of the RAP complex, RAP-1 and -3 in processes resulting in anaemia. Antibodies to the RAP complex were shown to have the potential to mediate the destruction of RAP-2-tagged erythroid cells by phagocytosis or by complement activation and lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the apoptotic death of RAP-2- tagged erythroblasts. The frequency and functionality of naturally occurring RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children were also investigated. All sera tested contained RAP-2-reactive antibodies by both immunofluorescence and flow cytometry. The anaemic group of children had higher levels of IgG than the non-anaemic ones, while the levels of IgM were similar. With respect to IgG subclasses, higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. The non-anaemic individuals recognised a greater proportion of RAP-2-tagged RBCs and activated complement to a greater extent than the anaemic ones.

Earlier studies observed that humans continuously exposed to malaria, recognised Pf332 extensively. Further studies revealed that Pf332 antibodies were able to inhibit parasite growth and cytoadherence in vitro. Making use of Pf332-C231, a sub-fragment of Pf332, we studied the effects/mode of action of C231-specific antibodies on P. falciparum parasite growth and development in vitro. The antibodies appeared to act mainly on late stage parasites by two main mechanisms: 1) through the induction of abnormal/pyknotic parasites, and, 2) RBC lysis (disintegration of RBCs), thus limiting parasite growth and development. The antibody isotype in this context was IgG. Following the removal of immune pressure, parasites resumed growth, albeit at a much slower rate. The results suggest that during natural infections, antibodies to C231 could play a role in parasite control.

In summary, these data suggest that antibodies to both antigens could be instrumental in immune responses leading to disease control, but could also mediate pathology.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2011. 94 p.
Keyword
immunity, malaria, RBCs, anaemia
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-57255 (URN)978-91-7447-284-4 (ISBN)
Public defence
2011-06-14, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following publication was unpublished and had a status as follows: Paper 3: Manuscript.Available from: 2011-05-12 Created: 2011-05-04 Last updated: 2011-08-22Bibliographically approved

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