Background
Methods
Results
Studies identified
GEO series | Title of dataset | Publication | Design | Infection/antigenic Stimulation | Species | Tissue | Age | Participant origin | Expression profiling | Subjects (samples)a | Controls | Platform name | Platform technology |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
GSE2900 | Host response malaria | Griffiths et al. (2005) | Comparison of GEP in febrile children with convalescent samples 2 weeks post discharge | Field | P. falciparum | Whole blood: PAX gene | Children 2–126 months | Kenya | Array | 22 (28) | Subject paired samples: diagnosis and post treatment | LC-36 | Spotted DNA/cDNA |
GSE5418 | Gene expression analysis in malaria infection | Ockenhouse et al. (2006) | Comparison of GEP in early, pre-symptomatic blood-stage infection post CHMI with symptomatic malaria-experienced adults with naturally acquired malaria | CHMI and Field | P. falciparum | PBMC | Adults; 19–49 years | USA and Cameroon | Array | 37 (74) | 22 un-infected malaria-naïve American adults | Affymetrix human genome U133A array | In situ oligonucleotide |
GSE15221 | Malaria primes the innate immune response due to IFNγ induced enhancement of Toll-like receptor expression and function | Franklin et al. (2009) and Sharma et al. (2011) and Hirako et al. (2018) | Comparison GEP at malaria diagnosis and 28 days post treatment | Field | P. falciparum | PBMC | Adults 30 ± 10 years | Brazil; Porto Velho | Array | 21 (42) | Subject paired samples: diagnosis and post treatment | Illumina human-6 v2.0 | Oligonucleotide beads |
GSE26876 | Time kinetics of gene expression in NK92 cells after P. falciparum-iRBC encounter | De Carvalho et al. (2011) | Comparison of GEP variation of NK92 cells after 6, 12, and 24 h of co-culture with either infected or uninfected RBC compared to time-point 0 | In vitro—iRBC | P. falciparum | NK92 cell line | N/A | N/A | Array | N/A (12) | Paired samples: pre and post exposure | Affymetrix human gene 1.0 ST array | In situ oligonucleotide |
GSE33811 | Paired whole blood human transcription profiles from children with severe malaria and mild malaria | Krupka et al. (2012) | Comparison of GEP in severe malaria and subsequent mild malaria in same subjects 1 month later | Field | P. falciparum | Whole blood: tri-reagent BD | Children: 8–45 months | Malawi | Array | 5 (10) | Subject paired samples: severe and mild malaria | Affymetrix Human Gene 1.0 ST Array | In situ oligonucleotide |
GSE34404 | The genomic architecture of host whole blood transcriptional response to malaria infection | Idaghdour et al. (2012) | Comparison of GEP in mild malaria with age matched un-infected controls | Field | P. falciparum | Whole blood: Tempus | Children; median age 3.7 years | Benin | Array | 94 subjects (94) and 64 controls (64) | Uninfected age matched | Illumina HumanHT-12 V4.0 expression bead chip | Oligonucleotide beads |
GSE55843 | Loss and dysfunction of Vdelta2 + gamma delta-low T cells is associated with clinical tolerance to malaria | Jagannathan et al. (2014) | Comparison of GEP of Vδ2 + T cells from children with ‘high’ and ‘low’ episodes of malaria in the preceding year | In vitro—iRBC | P. falciparum | Vδ2 + T cells | Children: 4–5 years | Uganda | Array | 78 (156) | N/A | Agilent-039494 SurePrint G3 Human GE v2 8 × 60K Microarray 03938 | In situ oligonucleotide |
GSE53292 | Transcriptomic analysis of Plasmodium PBANKA, PBSLTRiP-KO, PB268-KO parasite infected and uninfected host cell | Jaijyan et al. (2015) | Comparison of GEP of uninfected HepG2 with those infected with wild-type and knock out sporozoites | In vitro—sporozoites | P. falciparum | HepG2 cells | N/A | N/A | High throughput sequencing | NK | NK | Illumina Genome Analyzer IIx (Homo sapiens) | High-throughput sequencing |
GSE50957 | Molecular hallmarks of experimentally acquired immunity to malaria [Pilot Study] | Tran et al. (2016) and Vallejo et al. (2018) | Comparison of GEP pre and post infection | CHMI | P. falciparum | Whole blood: PAX gene | Adults: 19–22 years | USA | High throughput sequencing | 5 (10) | Subject paired samples: Pre and post infection | Illumina HiSeq 2000 (Homo sapiens) | High-throughput sequencing |
GSE52166 | Molecular hallmarks of naturally acquired immunity to malaria | Tran et al. (2016) | Comparison of GEP pre and post infection | Field | P. falciparum | Whole blood: Tempus | Adults and Children 13.5–23.3 years | Malawi | High throughput sequencing | 8 (16) | Paired same subject pre infection | Illumina HiSeq 2000 (Homo sapiens) | High-throughput sequencing |
GSE64338 | Expression data from whole blood samples of Rwandan adults with mild malaria with matched sample 30 days later (convalescence) | Subramaniam et al. (2015) | Comparison of GEP in mild malaria and 30 days later | Field | P. falciparum | Whole blood: Tri-Reagent BD | Adults | Rwandan | Array | 19 (38) | Subject paired samples: diagnosis and post treatment | [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array | In situ oligonucleotide |
GSE64493 | FCRL5 delineates functionally impaired memory B cells associated with malaria exposure | Sullivan (2015) | Comparison of GEP between classical and atypical memory B cells in Uganda children | Field | P. falciparum | PBMC | Children 8–10 years | Uganda | Array | 12 | NK | Agilent-039494 SurePrint G3 Human GE v2 8 × 60K Microarray 039381 | In situ oligonucleotide |
GSE67184 | Transcription profiling of malaria-naïve and semi-immune colombian volunteers in a Plasmodium vivax sporozoite challenge | Rojas-Penas (2015), Vallejo (2018) and Gardinassi (2018) | Comparison of GEP changes between malaria naïve and semi-immune adults pre-infection and at diagnosis | CHMI | P. vivax | Whole blood: Tempus | Adults | Columbia | High throughput sequencing | 12 (24) | Subject paired samples: pre-infection and diagnosis | Illumina HiSeq 2500 (Homo sapiens) | High-throughput sequencing |
GSE67469 | Transcription profiling of malaria-naïve and semi-immune colombian volunteers in a Plasmodium vivax sporozoite challenge | Rojas-Penas (2015) | Comparison of GEP changes between malaria naïve and semi-immune adults over the time-course of malaria infection: pre-infection, day 5, day 7, day 9, diagnosis and month 4 | CHMI | P. vivax | Whole blood: Tempus | Adults | Columbia | RT-qPCR | 16 (85) | Subject paired samples: Pre infection and multiple time-points post infection | Fluidigm 96×96 nanofluidic arrays for 96 genes: blood informative transcripts | RT-PCR |
GSE7586 | Genome wide analysis of placental malaria | Muehlenbachs (2007) | Comparison of GEP in women with placental malaria and those without | Field | P. falciparum | Placenta | Adults | Tanzania | Array | 20 (20) | NK | [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array | In situ oligonucleotide |
GSE77122 | Involvement of β-defensin 130 (DEFB130) in the macrophage microbicidal mechanisms for killing Plasmodium falciparum | Terkawi (2017) | Human monocyte-derived macrophages were co-cultured with P. falciparum iRBCs, saponin-treated iRBCs, or non-infected RBCs | In vitro—iRBC | P. falciparum | Macrophages | NK | NK | Array | NK (8) | NK | Agilent-028004 SurePrint G3 Human GE 8 × 60K Microarray | In situ oligonucleotide |
GSE93664 | Comparison of the transcriptomic profile of P. falciparum reactive polyfunctional and IFNγ monofunctional human CD4 T cells | Burel (2017) | Comparison of GEP in monofunctional and polyfunctional IFN producing T cells collected 21 days post CHMI infection | CHMI + in vitro—iRBC | P. falciparum | IFN producing T cells | 18–42 years | Australia | Array | 8 (2) | NK | [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array | In situ oligonucleotide |
GSE100562 | RNA-sequencing analysis of response to P. falciparum infection in Fulani and Mossi ethnic groups, Burkina Faso | Quin (2017) | Comparison of GEP in onocytes and CD14− cells in P. falciparum infected and uninfected malaria-exposed Fulani and Mossi sympatric ethnic groups | Field | P. falciparum | Monocytes (CD14+) and lymphocytes (CD14−) | 15–24 years | Burkino Faso | High throughput sequencing | 23 (23) | NK | Illumina HiSeq 2500 (Homo sapiens) | High-throughput sequencing |
GSE1124 | Whole blood transcriptome of childhood malaria | Boldt (2019) | Comparison of GEP of children with asymptomatic parasitemia, uncomplicated malaria, malaria with severe anaemia and cerebral malaria | Field | P. falciparum | Whole blood: PAX gene | 0.5–6 years | Gabon | Array | NK | Healthy control children | [HG-U133A] Affymetrix Human Genome U133A Array | In situ oligonucleotide |
GSE114076 | Differential gene expression profile of human neutrophils cultured with Plasmodium falciparum-parasitized erythrocytes | Terkawi (2018) | Comparison of GEP in neutrophils incubated with iRBC or non-infected RBC | In vitro—iRBC | P. falciparum | Neutrophils | NK | NK | Array | 1 (8) | Culture with non-infected RBC | Agilent-072363 SurePrint G3 Human GE v3 8 × 60K Microarray | In situ oligonucleotide |
GSE97158 | Transcriptional responses induced by controlled human malaria infection (CHMI) | Rothan (2018) | Comparison of GEP in whole blood pre and post sporozoite CHMI in malaria exposed adults | CHMI | P. falciparum | Whole blood: PAX gene | Adults | Tanzania | High throughput sequencing | 10 (40) | Subject paired samples: pre and post CHMI | Illumina HiSeq 2000 (Homo sapiens) | High-throughput sequencing |
GSE65928 | Malaria-associated atypical memory B cells exhibit markedly reduced B cell receptor signaling and effector function | Portugal (2015) | Comaprison of GEP of naïve B cells, classical and atypical memory B cells in immune adults | Field | P. falciparum | B cells | Adults: 18–37 years | Mali | Array | 20 (20) | US healthy adults | [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] | In situ oligonucleotide |
GSE72058 | Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in Malawian children | Feintuch (2016) | Comparison of GEP in cerebral malaria between children with malaria retinopathy and those without | Field | P. falciparum | Whole blood: Tri-Reagent BD | Children 6 month–12 years | Mali | Array | 98 (98) | NK | [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] | In situ oligonucleotide |
Review of methodological approaches
Dataset | Data generation | Gene ontology analysis | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
GEO series | Publication | RNA Quantification Platform | Normalization | Adjustment for covariates | Definition expression | Expressed genes | Threshold FC | Threshold P | Test | Multiple testing | GO analysis | Threshold GO enrichment p | Test | Multiple testing |
GSE2900 | Griffiths (2005) | Stanford University cDNA lymphochip two color microarray | Scaled to geometric mean of sample:reference signal ratio from all array features | NS | Signal threshold | 9869 | 2.5 (from median in > 4 samples) | 0.1 | Permutation | FDR | NA | NA | NA | NA |
GSE5418 | Ockenhouse (2006) | Affymetrix U133A GeneChips | RMA | NS | NS | NS | No | 0.01 | SAM, t-test | FDR | Onto Express and Pathway Architect | 0.05 | NS | FDR |
GSE15221 | Franklin (2009) and Sharma (2011) | Illumina Human WG-6 v2.0 | Cubic spline | NS | Signal threshold | NS | 1.7 | 0.01 | Paired t-test | FDR | Onto Express | Varying | NS | NS |
GSE15221 | Hirako (2018) | Illumina Human WG-6 v2.0 | Cubic spline | NS | Signal threshold | NS | 1.5 | 0.01 | Permutation and t-test | FDR | DAVID, GSEA | 0.05 | Multiple | FDR |
GSE26876 | de Carvalho (2011) | Affymetrix Human Gene 1.0 ST Array | RMA | NS | NS | NS | 1.5 | 0.05 | Student t-test | No | Ingenuity pathway analysis | NS | NS | NS |
GSE33811 | Krupka (2012) | Affymetrix Human Gene 1.0 ST Array | RMA and Quantile | NS | Signal and variation threshold | 3110 | 2 | 0.05 | Paired t-test | No | Gene set enrichment analysis on selected GO terms | 0.01 | Paired t-test | FDR |
GSE34404 | Idaghdour (2012) | Illumina Human HT-12 BeadChips | Quantile | Location, Sex, Hb, total cell counts (RBCs and WBCs) and ancestry | Signal and normality threshold | NS | 2 (for comparison) | 0.01 | ANOVA, ANCOVA | FDR | Gene set enrichment analysis on customized MsigDB database | 0.05 | NS | Bonferroni |
GSE55843 | Jagannathan (2014) | Agilent Sure Print G3 Human Gene Expression 8 × 60K v2 gene expression microarrays | Quantile | NS | Signal threshold | NS | 2 | 0.05 | SAM | FDR | NA | NA | NA | NA |
GSE53292 | Jaijyan (2015) | Illumina Genome Analyzer Iix 72SE | NS | NS | NS | NS | NS | 0.05 | t-test | No | GeneCodis3, Bingo 2.3 plugin (Cytoscape 2.8.3) | 0.05 | NS | NS |
GSE50957 GSE52166 | Tran (2016) | Illumina HiSeq 2000 2 × 100 PE | TAMM | Batch, Sex, Age, Pre-infection baseline | Signal and variation threshold, removal Y chromosomes | NS | 1.5 | 0.05 | Limma | FDR | Ingenuity pathway analysis | 0.05 | Fisher exact test | FDR |
GSE50957 GSE67184 | Vallejo (2018) | Illumina HiSeq 2000 2 × 100 PE | CPM, TPM | NS | Signal threshold | NS | NS | 0.05 | EdgeR | FDR | WGSEA, ToppGene, STRING | 0.05 | Multiple | FDR |
GSE64338 | Subramaniam (2015) | Affymetrix Human Gene 1.0 ST Array | Nonlinear normalization based on Li-Wong methods | NS | NS | NS | 1.2 | 0.001 | Paired t-test | FDR | Ingenuity Pathway Analysis | 0.05 | NS | FDR |
GSE64493 | Sullivan (2015) | Agilent Sure Print G3 Human Gene Expression 8 × 60K v2 gene expression microarrays | Quantile | NS | Signal threshold | NS | 1.5 | 0.03 | Limma | FDR | DAVID | 0.05 | NS | FDR |
GSE67184 | Rojas-Penas (2015) | Illumina HiSeq 2500 2 × 100 PE | SNM | Location/time-point, subject (random effect) | Signal threshold | 6154 | No | 0.05 | NS | FDR | NA | NA | NA | NA |
GSE67184 | Gardinassi (2018) | Illumina HiSeq 2500 2 × 100 PE | NS | NS | NS | NS | No | 0.05 | Limma, repeated measures ANOVA | FDR | GSEA on blood transcriptome modules (BTM, Li et al.) | 0.05 | permutation | FDR |
GSE7586 | Muehlenbachs (2007) | Affymetrix U133 Plus 2.0 GeneChip | GC RMA | NS | NS | NS | 2.5 | 0.01 | t-test | No | NA | NA | NA | NA |
GSE77122 | Tarawa (2017) | Agilent Sure Print G3 Human Gene Expression 8 × 60K gene expression microarrays | Each gene expression array dataset was normalized to the in silicon pool for the macrophages cultured with RBCs | NS | NS | NS | No | 0.05 | Paired t-test | No | DAVID | 0.05 | Fisher exact test | No |
GSE93664 | Burl (2017) | Affymetrix Human Gene ST 2.0 gene array | RMA | NS | NS | NS | 2 | 0.05 | NS | No | STRING | 0.01 | NS | Corrected unspecified |
GSE100562 | Quin (2017) | Illumina HiSeq 2500 2 × 50 PE | NS | NS | NS | NS | No | 0.05 | Limma | FDR | NA | NA | NA | NA |
GSE1124 | Boldt (2019) | Affymetrix U133A + B GeneChips | RMA | NS | Signal threshold | NS | 1.9 | 0.004 | SAM | FDR | DAVID and Ingenuity Pathway Analysis | 0.05 | NS | NS |
GSE114076 | Terkawi (2018) | Agilent Sure Print G3 Human Gene Expression 8 × 60K gene expression microarrays | Each gene expression array dataset was normalized to the in silicon pool for the neutrophils cultured with RBCs | NS | NS | NS | 2 | 0.01 | Limma | No | Genomatix GeneRanker, DAVID, NET-GE and Enricher | 0.05 | NS | Corrected unspecified |
GSE97158 | Rothan (2018) | Illumina HiSeq 2500 2 × 51 PE | TMM | Blocking by subject, in two separate models interaction with cell count and time of parasitemia was added | Signal threshold | 16,473 | 1.5 | 0.05 | Limma | FDR | GSEA (camera) on blood transcriptome modules (BTM, Li et al.) | 0.05 | Fisher exact test | FDR |
GSE65928 | Portugal (2015) | Affymetrix Human Gene ST 2.0 gene array | RMA | NS | NS | NS | NS | 0.05 | ANOVA | FDR | Ingenuity pathway analysis | NS | NS | NS |
GSE72058 | Feintuch (2016) | Affymetrix Human Gene 1.0 ST array | RMA and Quantile | Peripheral parasitemia | NS | NS | No | 0.05 | t-test | No | GSEA, CateGOrizer and ingenuity pathway analysis | 0.2 and 0.06 | NS | FDR |
Transcriptional insights into the immune response to malaria infection
Measure of NAI | Publication | Design | Sample | Species | Subjects for comparison | Key finding | Comment | |
---|---|---|---|---|---|---|---|---|
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 |