Abstract
Although the spleen is broadly accepted as the major lymphoid organ involved in generating immune responses to the erythrocytic stages of the malaria parasite, Plasmodium, human splenic tissue is not readily available in most cases. As a result, most studies of malaria in humans rely on peripheral blood to assess cellular immune responses to malaria. The suitability of peripheral blood as a proxy for splenic immune responses is however unknown. Here, we have simultaneously analysed the transcriptomes of whole blood and spleen over 12 days of erythrocytic stage Plasmodium chabaudi infection in C57BL/6 mice. Using both unsupervised and directed approaches, we compared gene expression between blood and spleen over the course of infection. Taking advantage of publicly available datasets, we used machine learning approaches to infer cell proportions and cell-specific gene expression signatures from our whole tissue transcriptome data. Our findings demonstrate that spleen and blood are quite dissimilar, sharing only a small amount of transcriptional information between them, with transcriptional differences in both cellular composition and transcriptional activity. These results suggest that while blood transcriptome data may be useful in defining surrogate markers of protection and pathology, they should not be used to predict specific immune responses occurring in lymphoid organs.
Highlights
The spleen is broadly accepted as the major lymphoid organ involved in generating immune responses to the erythrocytic stages of the malaria parasite, Plasmodium, human splenic tissue is not readily available in most cases
It is widely accepted that the majority of immune processes involved in the control of Plasmodium infection occur in the spleen[3,4], studies requiring human splenic tissue are not practical
The acute blood-stage infection of Plasmodium chabaudi chabaudi AS (PcAS) from which these blood and spleen samples were taken is described in detail in a previous publication[17]
Summary
The spleen is broadly accepted as the major lymphoid organ involved in generating immune responses to the erythrocytic stages of the malaria parasite, Plasmodium, human splenic tissue is not readily available in most cases. Most studies rely on the detection of immune signatures in peripheral blood to evaluate the performance of vaccine candidates[5,6], or to identify markers of protective immunity or pathology in humans[7,8,9] Despite this obvious discrepancy and mounting evidence of tissue-specific differences in gene expression during immune responses[10,11], there has not been a comprehensive analysis of simultaneous measurements from blood and spleen over the course of a Plasmodium infection to evaluate how similar or dissimilar the immune signatures in these two tissues are. We have used the malaria model of Plasmodium chabaudi infection in C57BL/6 mice to compare the transcriptomes of whole blood and spleen during first 12 days of an erythrocytic-stage infection using mouse microarrays To this end, we used an integrative approach applying statistical learning methods to analyse these transcriptomes, exploring the day-to-day transcriptional changes occurring in each tissue, allowing us to distinguish between conserved and tissue-specific immune responses to infection. We inferred the cellular composition of each tissue, allowing us to monitor the signature of transcriptional activity of individual immune cell populations within blood or spleen
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