Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria

Abstract

BackgroundThe development and outcome of cerebral malaria (CM) reflects a complex interplay between parasite-expressed virulence factors and host response to infection. The murine CM model, Plasmodium berghei ANKA (PbA), which simulates many of the features of human CM, provides an excellent system to study this host/parasite interface. We designed "combination" microarrays that concurrently detect genome-wide transcripts of both PbA and mouse, and examined parasite and host transcriptional programs during infection of CM-susceptible (C57BL/6) and CM-resistant (BALB/c) mice.ResultsAnalysis of expression data from brain, lung, liver, and spleen of PbA infected mice showed that both host and parasite gene expression can be examined using a single microarray, and parasite transcripts can be detected within whole organs at a time when peripheral blood parasitemia is low. Parasites display a unique transcriptional signature in each tissue, and lung appears to be a large reservoir for metabolically active parasites. In comparisons of susceptible versus resistant animals, both host and parasite display distinct, organ-specific transcriptional profiles. Differentially expressed mouse genes were related to humoral immune response, complement activation, or cell-cell interactions. PbA displayed differential expression of genes related to biosynthetic activities.ConclusionThese data show that host and parasite gene expression profiles can be simultaneously analysed using a single "combination" microarray, and that both the mouse and malaria parasite display distinct tissue- and strain-specific responses during infection. This technology facilitates the dissection of host-pathogen interactions in experimental cerebral malaria and could be extended to other disease models.

P. falciparum Modulates Erythroblast Cell Gene Expression in Signaling and Erythrocyte Production Pathways

“…al [29] into IPA. For Toxoplasma gondii infection of human foreskin fibroblasts, we imported genes listed in Figure 2 from Blader, et.…”

Genes involved in host–parasite interactions can be revealed by their correlated expression

“…To do this, we required a simultaneous gene expression time-course experiment where gene expression is measured at the same time points in interacting species. A small number of existing studies have generated such data, encompassing several different host–pathogen pairs (16,20,32–35). Two of these studies investigated the rodent malaria model P. berghei using a combined microarray to examine both the parasite and murine host (16), or parasite and mosquito vector (20), respectively.…”

“…The probe sequences from the Lovegrove et al (16) hybrid microarray were remapped to more recent versions of the Plasmodium berghei (July 2011; http://www.genedb.org) and mouse (NCBIM37; http://ensembl.org) genome assemblies using SMALT (Ponstingl, unpublished; http://www.sanger.ac.uk/resources/software/smalt/). Reads mapping to multiple locations were excluded, including those mapping to both genomes.…”

“…Where multiple probes mapped to a single gene, the mean intensity was taken for each time point. We used per-probe normalized BALB/c mouse intensity profiles as used in (16) and kindly provided by L. Peña-Castillo.…”

Comparative Genomics and Systems Biology of Malaria Parasites Plasmodium

“…The microarray chips for other Plasmodium species/strains, including P. berghei [5], P. yoelii [110, 111], P. vivax [112] have also been developed. Transcriptomic profiling is becoming one of the most powerful means of elucidating complex mechanisms that were previously impossible or difficult to study [113], including the mechanisms of cell cycle regulation [114], transcriptional control under various conditions [5, 115–120], gene silencing [121], genetic diversity, drug action and drug resistance [122–133], parasite invasion [134], pathogenesis and virulence [135–142], vector-parasite and host-parasite interactions [140, 143, 144], and sexual development [145]. The results have lead to the identification of novel drug and vaccine targets [47, 146–151].…”