Meta-analysis of Plasmodium falciparum <i>var</i> Signatures Contributing to Severe Malaria in African Children and Indian Adults.

30 Apr 2019
Duffy F, Bernabeu M, Babar PH, Kessler A, Wang CW, Vaz M, Chery L, Mandala WL, Rogerson SJ, Taylor TE, Seydel KB, Lavstsen T, Gomes E, Kim K, Lusingu J, Rathod PK, Aitchison JD, Smith JD

The clinical presentation of severe malaria differs between children and adults, but the mechanistic basis for this remains unclear. Contributing factors to disease severity include total parasite biomass and the diverse cytoadhesive properties mediated by the polymorphic gene parasite ligand family displayed on infected erythrocytes. To explore these factors, we performed a multicohort analysis of the contribution of expression and parasite biomass to severe malaria in two previously published pediatric cohorts in Tanzania and Malawi and an adult cohort in India. Machine learning analysis revealed independent and complementary roles for adhesion types and parasite biomass in adult and pediatric severe malaria and showed that similar profiles, including upregulation of group A and DC8 , predict severe malaria in adults and children. Among adults, patients with multiorgan complications presented infections with significantly higher parasite biomass without significant differences in adhesion types. Conversely, pediatric patients with specific complications showed distinct signatures. Cerebral malaria patients showed broadly increased expression of genes, in particular group A and DC8 , while children with severe malaria anemia were classified based on high transcription of DC8 only. This study represents the first large multisite meta-analysis of expression, and it demonstrates the presence of common profiles in severe malaria patients of different ages across distant geographical sites, as well as syndrome-specific disease signatures. The complex associations between parasite biomass, adhesion type, and clinical presentation revealed here represent the most comprehensive picture so far of the relationship between cytoadhesion, parasite load, and clinical syndrome. malaria can cause multiple disease complications that differ by patient age. Previous studies have attempted to address the roles of parasite adhesion and biomass in disease severity; however, these studies have been limited to single geographical sites, and there is limited understanding of how parasite adhesion and biomass interact to influence disease manifestations. In this meta-analysis, we compared parasite disease determinants in African children and Indian adults. This study demonstrates that parasite biomass and specific subsets of genes are independently associated with detrimental outcomes in both childhood and adult malaria. We also explored how parasite adhesion types and biomass play different roles in the development of specific severe malaria pathologies, including childhood cerebral malaria and multiorgan complications in adults. This work represents the largest study to date of the role of both adhesion types and biomass in severe malaria.