Whole blood transcriptome changes following controlled human malaria infection in malaria pre-exposed volunteers correlate with parasite prepatent period.

Julian Rothen,Maxmillian Mpina,Ken Stuart,Salim Abdulla,B Kim Lee Sim,Marcel Tanner,Stephen L Hoffman,Jason Carnes,Atashi Anupama,Carl Murie,Mwajuma Chemba,Raphael Gottardo,Claudia Daubenberger

doi:10.1371/journal.pone.0199392

Abstract

Malaria continues to be one of mankind’s most devastating diseases despite the many and varied efforts to combat it. Indispensable for malaria elimination and eventual eradication is the development of effective vaccines. Controlled human malaria infection (CHMI) is an invaluable tool for vaccine efficacy assessment and investigation of early immunological and molecular responses against Plasmodium falciparum infection. Here, we investigated gene expression changes following CHMI using RNA-Seq. Peripheral blood samples were collected in Bagamoyo, Tanzania, from ten adults who were injected intradermally (ID) with 2.5x104 aseptic, purified, cryopreserved P. falciparum sporozoites (Sanaria® PfSPZ Challenge). A total of 2,758 genes were identified as differentially expressed following CHMI. Transcriptional changes were most pronounced on day 5 after inoculation, during the clinically silent liver phase. A secondary analysis, grouping the volunteers according to their prepatent period duration, identified 265 genes whose expression levels were linked to time of blood stage parasitemia detection. Gene modules associated with these 265 genes were linked to regulation of transcription, cell cycle, phosphatidylinositol signaling and erythrocyte development. Our study showed that in malaria pre-exposed volunteers, parasite prepatent period in each individual is linked to magnitude and timing of early gene expression changes after ID CHMI.

Highlights

Malaria caused by Plasmodium falciparum continues to be one of mankind’s most devastating infectious diseases despite the many and varied efforts to combat it
The six pairwise comparisons identified a total of 2,758 unique genes or 16.7% of the total 16,473 genes contained in the data set that were differentially expressed
This study demonstrates that the wide window of parasite prepatent periods in Tanzanian volunteers, most likely due to different levels of pre-existing immunity or natural resistance, is of importance in evaluating transcriptional responses to controlled human malaria infection (CHMI)

Summary

Introduction

Malaria caused by Plasmodium falciparum continues to be one of mankind’s most devastating infectious diseases despite the many and varied efforts to combat it. Experimental vaccines comprised of live attenuated P. falciparum sporozoites have gained increased attention because they are highly effective in providing sterile immunity, i.e. immunity to infection [3,4,5,6,7,8,9,10,11,12,13] Such vaccines primarily targeting the pre-erythrocytic stage are safe because development of the parasite is arrested before, during or shortly after the liver stage, prior to the blood stage during which malaria disease symptoms occur. The latter is of particular importance given that we still lack a detailed understanding of the host responses to early stages of P. falciparum infection

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