Malaria exposure drives both cognate and bystander human B cells to adopt an atypical phenotype.

Racheal Aye,Eunice W Nduati,Jennifer Musyoki,Jedida Mwacharo,Edward Otieno,Juliana Wambua,Francis M Ndungu,Henry J Sutton,Ian A Cockburn,Philip Bejon,Oscar Kai

doi:10.1002/eji.201948473

Abstract

Atypical memory B cells (aMBCs) are found in elevated numbers in individuals exposed to malaria. A key question is whether malaria induces aMBCs as a result of exposure to Ag, or non-Ag-specific mechanisms. We identified Plasmodium and bystander tetanus toxoid (TT) specific B cells in individuals from areas of previous and persistent exposure to malaria using tetramers. Malaria-specific B cells were more likely to be aMBCs than TT-specific B cells. However, TT-specific B cells from individuals with continuous exposure to malaria were more likely to be aMBCs than TT-specific B cells in individuals from areas where transmission has ceased. Finally, sequences of BCRs specific for a blood stage malaria-Ag were more highly mutated than sequences from TT-specific BCRs and under strong negative selection, indicative of ongoing antigenic pressure. Our data suggest both persistent Ag exposure and the inflammatory environment shape the B-cell response to malaria and bystander Ags.

Highlights

Malaria, caused by parasites of the genus Plasmodium, was responsible for the deaths of 405,000 people in 2018 [1]
We focussed on three Plasmodium falciparum (Pf) Ags: the circumsporozoite protein (PfCSP) NANP peptide with nine repeats, which contain the B-cell epitopes for the PfCSP protein coating the surface of the infectious Pf sporozoite stage; merozoite surface protein 1 (PfMSP1) which is a blood stage Ag; and apical membrane Ag 1 (PfAMA1) which is expressed in both sporozoites and blood stages
Analysis of Ab responses revealed that antibodies to the blood stage Ags, PfAMA1 and PfMSP1, but not PfCSP were significantly higher in the persistently exposed compared to previously exposed adults (Fig. 1B)

Summary

Introduction

Malaria, caused by parasites of the genus Plasmodium, was responsible for the deaths of 405,000 people in 2018 [1]. A characteristic feature of the epidemiology of malaria is the fact that individuals who recover from infection do not develop sterilising immunity [2]. Children continually exposed to malaria transmission develop anti-disease immunity characterised by an overall reduction in the severity of symptoms during successive infections [2, 3]. Adults and older children rarely experience life-threatening severe disease; they remain susceptible to infection and to mild disease. Several hypotheses have been advanced to explain the lack of sterilising immunity. The parasite is highly polymorphic and undergoes antigenic variation meaning that the progressive

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Conclusion