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https://www.arca.fiocruz.br/handle/icict/57548
ANTIBODIES TO CRYPTIC EPITOPES IN DISTANT HOMOLOGUES UNDERPIN A MECHANISM OF HETEROLOGOUS IMMUNITY BETWEEN PLASMODIUM VIVAX PVDBP AND PLASMODIUM FALCIPARUM VAR2CSA
Plasmodium falciparum
Plasmodium vivax
PvDBP
VAR2CSA
cross-species
cryptic epitopes
epitopes
falciparum
heterologous immunity
malaria
pregnancy
vivax.
Autor(es)
Yanow, Stephanie K.
Mitran, Catherine J.
Mena, Angie
Gnidehou, Sedami
Banman, Shanna
Arango, Eliana
Lima, Barbara Andreza Soares
Lugo, Hazel
Ganesan, Aravindhan
Salanti, Ali
Mbonye, Anthony K
Ntumngia, Francis
Barakat, Khaled
Adams, John H
Kano, Flora Satiko
Carvalho, Luzia Helena
Maestre, Amanda E
Michael F, Good
Yanow, Stephanie K
Mitran, Catherine J.
Mena, Angie
Gnidehou, Sedami
Banman, Shanna
Arango, Eliana
Lima, Barbara Andreza Soares
Lugo, Hazel
Ganesan, Aravindhan
Salanti, Ali
Mbonye, Anthony K
Ntumngia, Francis
Barakat, Khaled
Adams, John H
Kano, Flora Satiko
Carvalho, Luzia Helena
Maestre, Amanda E
Michael F, Good
Yanow, Stephanie K
Afiliação
School of Public Health. University of Alberta. Edmonton, Alberta, Canada
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Department of Biology. Campus Saint-Jean University of Alberta. Edmonton, Alberta, Canada.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Grupo Salud y Comunidad. Facultad de Medicina. Medellín, Antioquia, Colombia.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Department of Immunology and Microbiology.Centre for Medical Parasitology. University of Copenhagen. Copenhagen, Denmark.
School of Public Health. Makerere University College of Health Sciences. Kampala, Uganda.
College of Public Health. University of South Florida. Tampa, Florida, USA.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
College of Public Health. University of South Florida. Tampa, Florida, USA.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Grupo Salud y Comunidad. Facultad de Medicina. Medellín, Antioquia, Colombia.
Institute for Glycomics. Griffith University. Southport, Queensland, Australia/Department of Medical Microbiology and Immunology. University of Alberta. Edmonton, Alberta, Canada.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada Australia/Department of Medical Microbiology and Immunology. University of Alberta. Edmonton, Alberta, Canada.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Department of Biology. Campus Saint-Jean University of Alberta. Edmonton, Alberta, Canada.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Grupo Salud y Comunidad. Facultad de Medicina. Medellín, Antioquia, Colombia.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Department of Immunology and Microbiology.Centre for Medical Parasitology. University of Copenhagen. Copenhagen, Denmark.
School of Public Health. Makerere University College of Health Sciences. Kampala, Uganda.
College of Public Health. University of South Florida. Tampa, Florida, USA.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
College of Public Health. University of South Florida. Tampa, Florida, USA.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
Grupo Salud y Comunidad. Facultad de Medicina. Medellín, Antioquia, Colombia.
Institute for Glycomics. Griffith University. Southport, Queensland, Australia/Department of Medical Microbiology and Immunology. University of Alberta. Edmonton, Alberta, Canada.
School of Public Health. University of Alberta. Edmonton, Alberta, Canada Australia/Department of Medical Microbiology and Immunology. University of Alberta. Edmonton, Alberta, Canada.
Resumo em Inglês
Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro. The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5 epsilon domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes.
IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium. Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.
Palavras-chave em inglês
PlasmodiumPlasmodium falciparum
Plasmodium vivax
PvDBP
VAR2CSA
cross-species
cryptic epitopes
epitopes
falciparum
heterologous immunity
malaria
pregnancy
vivax.
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