Table 3 Gene expression studies informing understanding of naturally acquired immunity to malaria infection

Prior exposure to malaria

Tran et al. (2016)

Comparison of GEP changes from paired infected and uninfected samples

Whole blood

P. falciparum

Malaria-naïve, symptomatic Dutch CHMI volunteers at diagnosis (n = 5)

Malaria experienced Malian children (> 13 years) and adults infected in the field (n = 8)

Graded activation of pathways of downstream proinflammatory cytokines with highest activation in malaria-naive subjects and significantly reduced activation in malaria experienced Malians

Ockenhouse et al. (2006)

Comparison of GEP changes in infection-controls samples US malaria naïve subjects

PBMC

P. falciparum

US malaria-naïve CHMI volunteers with early, blood-stage infection (n = 22)

Malaria-experienced Cameroonian adults presenting with naturally acquired febrile malaria (n = 15)

Similar induction of pro-inflammatory cytokines seen between pre-symptomatic and symptomatic individuals regardless of prior malaria exposure

Rojas-Pena et al. (2015) and Vallejo et al. (2018)

Comparison of GEP changes from paired infected and uninfected samples

Whole blood

P. vivax

Columbian malaria-naïve (MN) CHMI volunteers at diagnosis (n = 7)

Columbian malaria-exposed (ME) CHMI volunteers at diagnosis (n = 9)

Little differentiation seen between MN and ME populations by Rojas-Penas et al. However network co-expression analysis by Vallejo et al. showed the inflammatory response was attenuated in ME volunteers with decreased class II antigen presentation in dendritic cells

No significant difference between groups for pre-patent period or parasitaemia at diagnosis suggesting there may have been no difference in functional immunity between groups

Jagannathan et al. (2014)

Comparison of GEP between groups

Vδ2⁺ T cells

P. falciparum

Ugandan children with low prior malaria incidence (n = 4)

Ugandan children with low prior malaria incidence (n = 4)

Comparison of basal gene expression patterns of sorted, un-stimulated Vδ2⁺ T cells identified 48 differentially expressed genes, many with known roles in immunomodulation. For each of these genes, expression was higher among children with high prior exposure to malaria

Data suggest recurrent malaria infection causes up-regulation of immunoregulatory pathways that dampen the pro-inflammatory immune response to P. falciparum infection and help explain immunological tolerance to the parasite

Symptoms at diagnosis

Tran et al. (2016)

Comparison of GEP changes from paired infected and uninfected samples

Whole blood

P. falciparum

Malaria experienced Malian children (> 13 years) and adults infected in the field and asymptomatic at diagnosis (EA, n = 5)

Malaria experienced Malian children (> 13 years) and adults infected in the field and symptomatic with fever at the time of diagnosis (EF, n = 3)

Only 70 differentially expressed genes (DEGs) were identified between these groups despite the apparent clinical differences

2 of the 5 individuals in the EA group progressed to febrile malaria within 5 days of initial diagnosis by PCR

Disease severity

Krupka et al. (2012)

Comparison of GEP in same subjects at diagnosis with severe and subsequent mild malaria

Whole blood

P. falciparum

Malawian children who, after presenting with severe malaria (all had cerebral malaria), were found to have mild malaria one month later on screening by blood smear (n = 5)

Pathway analysis showed relative up regulation of Type I IFN signaling pathway, regulation of inflammation, regulation of leukocyte proliferation and T cell activation in episodes of mild malaria

Boldt et al. (2019)

Comparison of GEP between groups

Whole blood

P. falciparum

Healthy uninfected Gabonese children

Gabonese children with asymptomatic parasitaemia, mild malaria, malaria with severe anaemia and cerebral anaemia (0.5–6 years)

GEP of 22 genes significantly differed among groups. Immunoglobulin production, complement regulation and IFN beta signaling were most conspicuous