Repeat Sequences in Block 2 of<i>Plasmodium falciparum</i>Merozoite Surface Protein 1 Are Targets of Antibodies Associated with Protection from Malaria

Polley, Spencer D.; Tetteh, Kevin K. A.; Cavanagh, David; Pearce, R. P.; Lloyd, Jennifer M.; Bojang, Kalifa; Okenu, Daniel M. N.; Greenwood, Brian; McBride, Jana S.; Conway, David J.

doi:10.1128/iai.71.4.1833-1842.2003

Cited by 58 publications

(82 citation statements)

References 37 publications

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“…Our observation that MSP-1 19 induces a mixed IgG1/IgG3 response which then polarizes, with increasing exposure to infection, to IgG1 is consistent with previous reports (11,15,18,34), as is our observation that MSP-2 and GPI preferentially induce IgG3 antibodies (6,29,39,46). Polarized IgG1 responses are also reported for Pf155/RESA (17), crude schizont lysate (33), RAP-1 (44), and MSP-6 (50), while IgG3 responses are seen for a polymorphic C-terminal region (block 2) of MSP-1 (11), MSP-3 (11, 31), MSP-4 (51), and MSP-7 (50).…”

Section: Discussionsupporting

confidence: 82%

Target Antigen, Age, and Duration of Antigen Exposure Independently Regulate Immunoglobulin G Subclass Switching in Malaria

et al. 2006

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The isotype/subclass of immunoglobulin determines antibody function, but rather little is known about factors that direct class switching in vivo. To evaluate factors that might influence the maturation of the antibody response during infection, we conducted a seroepidemiological study of the immunoglobulin G (IgG) subclass response to four merozoite-associated antigens of Plasmodium falciparum in a mountainous region of northeastern Tanzania, where malaria endemicity declines with increasing altitudes. We found that IgG1/IgG3 class switching is independently affected by the nature of the antigen, cumulative exposure to the antigen, and the maturity of the immune system (i.e., the age of the individual). These observations provide insights into the effects of immune system maturity, the duration and intensity of antigen exposure, and inherent characteristics of individual antigens on the process of class switching in human B cells. Our data also throw light on the consequences of class switch decisions on the gradual acquisition of antimalarial immunity.The isotype/subclass of immunoglobulin determines antibody function (e.g., complement fixation or the activation of phagocytes), and in humans, immunoglobulin G1 (IgG1) and IgG3 are important mediators of pathogen clearance. Specific combinations of cytokines and B-cell activators have been shown to induce class switching to certain isotypes or subclasses in model systems (13), but less is known about factors that direct class switching in vivo during infection. While it has long been suspected that characteristics of antigens themselves influence class switching in B cells (41,43), and while some antigens induce characteristic patterns of Ig class switching, most notably (in humans) encapsulated bacteria (IgG2) (27, 28) and allergens and helminths (IgG4 and IgE) (20), the characteristics of antigens that induce switching to human IgG1 and IgG3 are not well described.Numerous studies have reported that IgG subclass profiles differ among antibodies targeted to different malarial antigens, with the best example being the tendency of merozoite surface protein 2 (MSP-2) to induce very strong IgG3 responses (39,46), in contrast to the tendency of the C terminus of MSP-1, MSP-1 19 , to induce IgG1 or a mixed IgG1/IgG3 response (7,18). Here we demonstrate that characteristics of antigens per se can regulate the IgG1/IgG3 class switch, in that different antigens of Plasmodium falciparum, the causative agent of the virulent form of human malaria, elicit entirely different antibody subclasses even though they are presented to the immune system at the same time and as part of the same single-celled organism (i.e., the malaria merozoite). To evaluate the effects of antigens per se, immune system maturity (age), and cumulative exposure to antigens (which varies according to the intensity of malaria transmission) on the maturation of the IgG response, we conducted a seroepidemiological study in a mountainous region of northeastern Tanzania, where malaria endemicity declines wi...

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Section: Discussionsupporting

confidence: 82%

Target Antigen, Age, and Duration of Antigen Exposure Independently Regulate Immunoglobulin G Subclass Switching in Malaria

et al. 2006

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“…Thus, early studies have demonstrated the presence of naturally acquired antibodies against the N terminus (7, 9) and C terminus (13,28,31) of PfMSP1. The presence of such naturally acquired antibodies against MSP1 was later correlated to clinical protection in some, though not all, studies (8,10,12,14,24,25,26). Although the role of other portions of this large molecule remains mostly unknown, these studies have validated the N and C termini of PfMSP1 as solid subunit vaccine candidates against P. falciparum.…”

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confidence: 85%

“…personally diagnosed these patients, and after obtaining ethical consent to not treat them with drugs, actively followed them up twice a week for 2 months to guarantee that they did not develop malaria symptoms. Moreover, we analyzed independently the N and C termini of PvMSP1, as antibodies against both regions of the MSP1 of P. falciparum have been associated with clinical protection and acquired immunity (8,10,12,14,24,25,26). Strikingly, in spite of being the most immunogenic portion of PvMSP1 in natural infections and being capable of boosting (34), there was no association of antibody responses against the C terminus of PvMSP1 in survey A with clinical protection or risk of P. vivax infection (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Reduced Risk of Infection with Plasmodium vivax and Clinical Protection against Malaria Are Associated with Antibodies against the N Terminus but Not the C Terminus of Merozoite Surface Protein 1

et al. 2006

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Progress towards the development of a malaria vaccine against Plasmodium vivax, the most widely distributed human malaria parasite, will require a better understanding of the immune responses that confer clinical protection to patients in regions where malaria is endemic. The occurrence of clinical protection in P. vivax malaria in Brazil was first reported among residents of the riverine community of Portuchuelo, in Rondônia, western Amazon. We thus analyzed immune sera from this same human population to determine if naturally acquired humoral immune responses against the merozoite surface protein 1 of P. vivax, PvMSP1, could be associated with reduced risk of infection and/or clinical protection. Our results demonstrated that this association could be established with anti-PvMSP1 antibodies predominantly of the immunoglobulin G3 subclass directed against the N terminus but not against the C terminus, in spite of the latter being more immunogenic and capable of natural boosting. This is the first report of a prospective study of P. vivax malaria demonstrating an association of reduced risk of infection and clinical protection with antibodies against an antigen of this parasite.Malaria remains one of the major public health problems in South and Central America, where Plasmodium vivax is the main species responsible for infections. Although malaria caused by this human parasite is not lethal, the clinical manifestations represent a major socioeconomical burden in the major cities and rural areas of the Brazilian Amazon, which contains 99.7% of all malaria cases. Although a few studies indicate that some cross-protection between Plasmodium vivax, the most widely distributed human malaria parasite, and P. falciparum, the most virulent species, does occur (33), immunity in malaria is mostly species specific; thus, it is likely that a vaccine against P. falciparum will not cross-protect against P. vivax. Progress is being made to develop P. vivax vaccines per se (for a review, see reference 2); however, to date there are no prospective studies associating human immune responses to any P. vivax antigen with clinical protection.The history of malaria in Brazil has been punctuated with epidemics associated with migration movements of nonimmune population to areas where malaria is endemic (20,30,36). Previous studies done in these epidemiological settings showed that Plasmodium infection was always associated with symptoms, and clinical protection was not observed (27). However, through a cross-sectional and longitudinal study among native Amazon residents of the riverine community of Portuchuelo in Rondônia, located in the western Brazilian Amazon, the occurrence of symptomless Plasmodium vivax-infected individuals was reported (1, 6). Symptomless Plasmodium infections were defined as individuals who contain parasites in their peripheral blood, as detected by Giemsa blood smears and/or PCR, and who were not drug treated yet did not develop clinical symptoms during a 2-month individual follow-up. These rigorous criteria...

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“…The sequence was subcloned from the pPCR-Script vector into pGEX-2T to be expressed as a glutathione S-transferase (GST) fusion protein in Escherichia coli BL21(DE3) cells. Expression and purification followed manufacturers' protocols, as described previously for other MSP1 block 2 recombinant proteins (5,32).…”

Section: Methodsmentioning

confidence: 99%

“…One of these, the K1-like type, is the most common in all African populations (7) and contains the most complex subtype sequence diversity due to variation in different tri-and hexapeptide repeat sequences (28). Although subtype-specific human antibodies to K1-like repeats have been described (4,5) and are associated with protection from clinical malaria (32), the adaptive significance of the extensive repeat sequence polymorphism is not clearly understood. The present study explores the statistical distribution of sequence length variation in different parts of the K1-like repeats and identifies the primary sequences that are recognized by murine monoclonal and human serum antibodies.…”

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confidence: 99%

Extensive Antigenic Polymorphism within the Repeat Sequence of thePlasmodium falciparumMerozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

et al. 2005

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Polymorphism in pathogen antigens presents a complex challenge for vaccine design. A prime example is the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP1), to which allele-specific antibodies have been associated with protection from malaria. In a Zambian population studied here, 49 of 91 alleles sampled were of the K1-like type (the most common of three block 2 types in all African populations), and most of these had unique sequences due to variation in tri-and hexapeptide repetitive motifs. There were significant negative correlations between allelic sequence lengths of different regions of the repeats, so the complete repeat sequence had less length variation than its component parts, suggesting a constraint on overall length. Diverse epitopes recognized by three murine monoclonal antibodies and 24 individual human sera were then mapped by using a comprehensive panel of synthetic peptides, revealing epitopes in all regions of the repeats. To incorporate these different epitopes in a single molecule, a composite sequence of minimal overall length (78 amino acids) was then designed and expressed as a recombinant antigen. More human immune sera reacted with this "K1-like Super Repeat" antigen than with proteins consisting of single natural allelic sequences, and immunization of mice elicited antibodies that recognized a range of five cultured parasite lines with diverse K1-like MSP1 block 2 repeat sequences. Thus, complex allelic polymorphism was deconstructed and a minimal composite polyvalent antigen was engineered, delivering a designed candidate sequence for inclusion in a malaria vaccine.

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Repeat Sequences in Block 2 ofPlasmodium falciparumMerozoite Surface Protein 1 Are Targets of Antibodies Associated with Protection from Malaria

Cited by 58 publications

References 37 publications

Target Antigen, Age, and Duration of Antigen Exposure Independently Regulate Immunoglobulin G Subclass Switching in Malaria

Target Antigen, Age, and Duration of Antigen Exposure Independently Regulate Immunoglobulin G Subclass Switching in Malaria

A Reduced Risk of Infection with Plasmodium vivax and Clinical Protection against Malaria Are Associated with Antibodies against the N Terminus but Not the C Terminus of Merozoite Surface Protein 1

Extensive Antigenic Polymorphism within the Repeat Sequence of thePlasmodium falciparumMerozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

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