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Transcription Profiling of Malaria-Naïve and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge.

Rojas-Peña ML, Vallejo A, Herrera S, Gibson G, Arévalo-Herrera M - PLoS Negl Trop Dis (2015)

Bottom Line: There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity.This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis.Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT

Background: Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology.

Methodology/principal findings: Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naïve individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali.

Conclusion/significance: Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity.

No MeSH data available.


Related in: MedlinePlus

Axis of variance analysis.Each plot shows the differences in Axis scores at 6 different timepoints for RT-qPCR (A and B) and two for RNASeq (C-E); Blue solid point represents Cali, and red open circles represent Buenaventura. P-values for the effect of timepoint including location as a fixed effect and individual as a random effect in the RNASeq data are 0.016 (Axis 2), 4.4×10-5 (Axis 5), 0.0003 (Axis 7).
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pntd.0003978.g003: Axis of variance analysis.Each plot shows the differences in Axis scores at 6 different timepoints for RT-qPCR (A and B) and two for RNASeq (C-E); Blue solid point represents Cali, and red open circles represent Buenaventura. P-values for the effect of timepoint including location as a fixed effect and individual as a random effect in the RNASeq data are 0.016 (Axis 2), 4.4×10-5 (Axis 5), 0.0003 (Axis 7).

Mentions: We confirmed that most of the genes were co-regulated in this dataset by observing a strong correlation of expression for each of the 10 BIT for each Axis, and then generated Axis scores as the first principal component of the variance of those 10 BIT. Only two of the Axes were differentially expressed among timepoints in the Fluidigm data (Fig 3A and 3B). Axis 5 is related to innate immune signaling and neutrophil number, and seems to decline at Diagnosis, surprisingly, implying a mild reduction in inflammatory gene activity. Axis 7 represents Type 1 interferon induction and is, as expected, elevated at diagnosis, reflecting a transient specific immune response. Both axes had returned to close to baseline levels three months after recovery. No other gene expression differences detected by this targeted RT-qPCR analysis were associated with time or population. These results are consistent with previously observed stable maintenance of peripheral blood gene expression profiles in healthy adults. A caveat to this analysis is that it is possible that other genes not included in the targeted set of probes do change in expression prior to the diagnosis of parasitemia, or alternatively do not return to baseline after recovery.


Transcription Profiling of Malaria-Naïve and Semi-immune Colombian Volunteers in a Plasmodium vivax Sporozoite Challenge.

Rojas-Peña ML, Vallejo A, Herrera S, Gibson G, Arévalo-Herrera M - PLoS Negl Trop Dis (2015)

Axis of variance analysis.Each plot shows the differences in Axis scores at 6 different timepoints for RT-qPCR (A and B) and two for RNASeq (C-E); Blue solid point represents Cali, and red open circles represent Buenaventura. P-values for the effect of timepoint including location as a fixed effect and individual as a random effect in the RNASeq data are 0.016 (Axis 2), 4.4×10-5 (Axis 5), 0.0003 (Axis 7).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526565&req=5

pntd.0003978.g003: Axis of variance analysis.Each plot shows the differences in Axis scores at 6 different timepoints for RT-qPCR (A and B) and two for RNASeq (C-E); Blue solid point represents Cali, and red open circles represent Buenaventura. P-values for the effect of timepoint including location as a fixed effect and individual as a random effect in the RNASeq data are 0.016 (Axis 2), 4.4×10-5 (Axis 5), 0.0003 (Axis 7).
Mentions: We confirmed that most of the genes were co-regulated in this dataset by observing a strong correlation of expression for each of the 10 BIT for each Axis, and then generated Axis scores as the first principal component of the variance of those 10 BIT. Only two of the Axes were differentially expressed among timepoints in the Fluidigm data (Fig 3A and 3B). Axis 5 is related to innate immune signaling and neutrophil number, and seems to decline at Diagnosis, surprisingly, implying a mild reduction in inflammatory gene activity. Axis 7 represents Type 1 interferon induction and is, as expected, elevated at diagnosis, reflecting a transient specific immune response. Both axes had returned to close to baseline levels three months after recovery. No other gene expression differences detected by this targeted RT-qPCR analysis were associated with time or population. These results are consistent with previously observed stable maintenance of peripheral blood gene expression profiles in healthy adults. A caveat to this analysis is that it is possible that other genes not included in the targeted set of probes do change in expression prior to the diagnosis of parasitemia, or alternatively do not return to baseline after recovery.

Bottom Line: There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity.This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis.Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali.

View Article: PubMed Central - PubMed

Affiliation: Center for Integrative Genomics, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT

Background: Continued exposure to malaria-causing parasites in endemic regions of malaria induces significant levels of acquired immunity in adult individuals. A better understanding of the transcriptional basis for this acquired immunological response may provide insight into how the immune system can be boosted during vaccination, and into why infected individuals differ in symptomology.

Methodology/principal findings: Peripheral blood gene expression profiles of 9 semi-immune volunteers from a Plasmodium vivax malaria prevalent region (Buenaventura, Colombia) were compared to those of 7 naïve individuals from a region with no reported transmission of malaria (Cali, Colombia) after a controlled infection mosquito bite challenge with P. vivax. A Fluidigm nanoscale quantitative RT-PCR array was used to survey altered expression of 96 blood informative transcripts at 7 timepoints after controlled infection, and RNASeq was used to contrast pre-infection and early parasitemia timepoints. There was no evidence for transcriptional changes prior to the appearance of blood stage parasites at day 12 or 13, at which time there was a strong interferon response and, unexpectedly, down-regulation of transcripts related to inflammation and innate immunity. This differential expression was confirmed with RNASeq, which also suggested perturbations of aspects of T cell function and erythropoiesis. Despite differences in clinical symptoms between the semi-immune and malaria naïve individuals, only subtle differences in their transcriptomes were observed, although 175 genes showed significantly greater induction or repression in the naïve volunteers from Cali.

Conclusion/significance: Gene expression profiling of whole blood reveals the type and duration of the immune response to P. vivax infection, and highlights a subset of genes that may mediate adaptive immunity.

No MeSH data available.


Related in: MedlinePlus