Research ArticleMalaria

Functional human IgA targets a conserved site on malaria sporozoites

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Science Translational Medicine  23 Jun 2021:
Vol. 13, Issue 599, eabg2344
DOI: 10.1126/scitranslmed.abg2344

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A role for IgA in malaria

Immunoglobulin (Ig)A is known to play a protective role against pathogens at mucosal surfaces. However, the protective effects of IgA in the serum are less well understood, particularly in the context of pathogens such as Plasmodium falciparum. To address this question, Tan et al. isolated and characterized serum IgA from three independent cohorts of humans exposed to P. falciparum. The authors further studied IgA antibodies isolated from individuals who were consistently resistant to malaria, finding that they were protective in mouse models in vivo and bound to a conserved site on sporozoites. Together, these results established a role for serum IgA in the context of malaria and identified a region of the circumsporozoite protein as a target for these protective antibodies.

Abstract

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

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