Mapping immune variation and var gene switching in naive hosts infected with Plasmodium falciparum.

Kathryn H Milne ,Navin Venkatraman,Alasdair Ivens,Matthew Berriman,Wiebke Nahrendorf,Geetha Sankaranarayanan,Áine O’toole ,Magda E Lotkowska ,Adam J Reid ,Clément Regnault ,Sarah E Silk ,J Alexandra Rowe ,Diana Muñoz Sandoval ,Ruth Payne ,Michael P Barrett ,Adrian V S Hill ,Nick J Edwards ,Angela M Minassian ,Mandy Sanders ,Simon J Draper ,Philip J Spence

doi:10.7554/elife.62800

Abstract

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease rapidly expand in naive hosts, we found no transcriptional evidence to support this hypothesis. These data indicate that parasite variants that dominate severe malaria do not have an intrinsic growth or survival advantage; instead, they presumably rely upon infection-induced changes in their within-host environment for selection.

Highlights

There is enormous diversity in the human response to identical immune challenge
We examined the hierarchy of var gene expression in the inoculum used for blood challenge; this derived from a single malariainfected volunteer infected by mosquito bite and was cryopreserved ex vivo after just three cycles of asexual replication (Cheng et al, 1997)
One leading hypothesis is that group A/DC8 variants have an intrinsic growth and/or survival advantage leading to their rapid expansion in naive hosts

Summary

Introduction

There is enormous diversity in the human response to identical immune challenge. This variation is currently being interrogated in large cohorts of healthy volunteers to pinpoint the genetic and nongenetic factors that dictate human immune decision-making (Bakker et al, 2018; Brodin et al, 2015; Li et al, 2016; Patin et al, 2018; Piasecka et al, 2018; Ter Horst et al, 2016). Controlled human malaria infection (CHMI) provides a well-established challenge model in which to examine immune variation in vivo, and heterogeneity in the host response to Plasmodium falciparum is wellrecognised (Roestenberg et al, 2012; Yap et al, 2020).

Methods

Results

Conclusion