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Differential immune response associated to malaria outcome is detectable in peripheral blood following Plasmodium yoelii infection in mice.

ABSTRACT: Malaria infection in humans elicits a wide range of immune responses that can be detected in peripheral blood, but we lack detailed long-term follow-up data on the primary and subsequent infections that lead to naturally acquired immunity. Studies on antimalarial immune responses in mice have been based on models yielding homogenous infection profiles. Here, we present a mouse model in which a heterogeneous course of Plasmodium yoelii lethal malaria infection is produced in a non-congenic ICR strain to allow comparison among different immunological and clinical outcomes. Three different disease courses were observed ranging from a fatal outcome, either early or late, to a self-resolved infection that conferred long-term immunity against re-infection. Qualitative and quantitative changes produced in leukocyte subpopulations and cytokine profiles detected in peripheral blood during the first week of infection revealed that monocytes, dendritic cells and immature B cells were the main cell subsets present in highly-parasitized mice dying in the first week after infection. Besides, CD4(+)CD25(high) T cells expanded at an earlier time point in early deceased mice than in surviving mice and expressed higher levels of intracellular Foxp3 protein. In contrast, survivors showed a limited increase of cytokines release and stable circulating innate cells. From the second week of infection, mice that would die or survive showed similar immune profiles, although CD4(+)CD25(high) T cells number increased earlier in mice with the worst prognosis. In surviving mice the expansion of activated circulating T cell and switched-class B cells with a long-term protective humoral response from the second infection week is remarkable. Our results demonstrate that the follow-up studies of immunological blood parameters during a malaria infection can offer information about the course of the pathological process and the immune response.

SUBMITTER: Azcarate IG

PROVIDER: S-EPMC3900426 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Differential immune response associated to malaria outcome is detectable in peripheral blood following Plasmodium yoelii infection in mice.

Azcárate Isabel G IG Marín-García Patricia P Kamali Alí N AN Pérez-Benavente Susana S Puyet Antonio A Diez Amalia A Bautista José M JM

PloS one 20140123 1

Malaria infection in humans elicits a wide range of immune responses that can be detected in peripheral blood, but we lack detailed long-term follow-up data on the primary and subsequent infections that lead to naturally acquired immunity. Studies on antimalarial immune responses in mice have been based on models yielding homogenous infection profiles. Here, we present a mouse model in which a heterogeneous course of Plasmodium yoelii lethal malaria infection is produced in a non-congenic ICR st ...[more]

PMID: 24465641

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Project description:The transmission of drug-resistant parasites by the mosquito may be influenced by the altered biological fitness of drug-resistant parasites and different immune reactions or metabolic change in the mosquito. At this point, little is known about the variations in mosquito immunity and metabolism when mosquitoes are infected with drug-resistant parasites. To understand the differential gene expression in Anopheles following infection with drug-resistant Plasmodium, we conducted a genome-wide transcriptomic profiling analysis of Anopheles stephensi following feeding on mice with drug-resistant or drug-sensitive P. yoelii, observed changes in gene expression profiles and identified transcripts affected by the drug-resistant parasite.To study the impact of drug-resistant Plasmodium infections on An. stephensi gene transcription, we analyzed the three major transition stages of Plasmodium infections: at 24 h and 13 and 19 days after blood-feeding. Six cDNA libraries (R-As24h, R-As13d, R-As19d,S-As24h, S-As13dand S-As19d) were constructed, and RNA sequencing was subsequently performed. In total, approximately 50.1 million raw reads, 47.9 million clean reads and 7.18G clean bases were obtained. Following differentially expressed gene (DEG) analysis, GO enrichment analysis of DEGs, and functional classification by KEGG, we showed that the variations in gene expression in An. stephensi infected by the drug-resistant P. yoelii NSM occurred mainly at 13 days after blood meal during sporozoite migration through the hemolymph. The differentially expressed genes included those functioning in some important immune reaction and iron metabolism pathways, such as pattern recognition receptors, regulators of the JNK pathway, components of the phagosome pathway, regulators of the melanization response, activators of complement reactions, insulin signaling cascade members, oxidative stress and detoxification proteins.Our study shows that drug-resistant P. yoelii NSM has an impact on the transcript abundance levels of An.stephensi mostly at 13 days after blood meal during sporozoite migration through the hemolymph and that most differentially expressed genes were downregulated. Our results highlight the need for a better understanding of selective pressures from these differentially expressed genes of the drug-resistant Plasmodium in the mosquito and the different transmission patterns of drug-resistant Plasmodium by Anopheles.

Project description:BackgroundMicroarray studies using in vitro cultures of synchronized, blood-stage Plasmodium falciparum malaria parasites have revealed a 'just-in-time' cascade of gene expression with some indication that these transcriptional patterns remain stable even in the presence of external stressors. However, direct analysis of transcription in P. falciparum blood-stage parasites obtained from the blood of infected patients suggests that parasite gene expression may be modulated by factors present in the in vivo environment of the host. The aim of this study was to examine changes in gene expression of the rodent malaria parasite, Plasmodium yoelii 17X, while varying the in vivo setting of replication.MethodsUsing P. yoelii 17X parasites replicating in vivo, differential gene expression in parasites isolated from individual mice, from independent infections, during ascending, peak and descending parasitaemia and in the presence and absence of host antibody responses was examined using P. yoelii DNA microarrays. A genome-wide analysis to identify coordinated changes in groups of genes associated with specific biological pathways was a primary focus, although an analysis of the expression patterns of two multi-gene families in P. yoelii, the yir and pyst-a families, was also completed.ResultsAcross experimental conditions, transcription was surprisingly stable with little evidence for distinct transcriptional states or for consistent changes in specific pathways. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability. However, the number of differentially expressed genes was generally low. Of genes that were differentially expressed, many involved biologically diverse pathways. There was little to no differential expression of members of the yir and pyst-a multigene families that encode polymorphic proteins associated with the membrane of infected erythrocytes. However, a relatively large number of these genes were expressed during blood-stage infection regardless of experimental condition.ConclusionsTaken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment, and 2) concurrent expression of a large number of the polymorphic yir and pyst-a genes, rather than differential expression in response to specific host factors, may in itself limit the effectiveness of host immune responses.

Project description:Microarray studies using synchronized Plasmodium falciparum parasites have revealed a ‘continuous cascade’ of gene expression. Reports vary regarding the stability in these transcriptional patterns in the presence of external stressors. Using Plasmodium yoelii 17X parasites replicating in vivo, we have examined differential gene expression in parasites isolated from individual mice, from independent infections, during ascending and peak parasitemia and in the presence and absence of host antibody responses. Across experimental conditions, transcription was surprisingly stable. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability; however, even these changes were modest. Of genes that were differentially expressed, many are of unknown function. There was little to no differential expression of members of the yir and pyst-a multigene families, although a relatively large number of these were expressed during blood-stage infection regardless of experimental condition. Taken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment and 2) concurrent expression of a large number of the yir and pyst-a genes may function to divert host immune responses away from invariant protective antigens. 1. P. yoelii 17X gene expression profiles were determined in blood-stage parasites isolated from infected Balb/c mice (male, 8-12 weeks old) as follows: a. Mouse 1 (M1), Mouse 2 (M2), Mouse 3 (M3), Donor (D) mouse – three mice simultaneously infected with P. yoelii 17X iRBCs from a single donor mouse. Parasite RNA was isolated early during infection when parasitemia was ascending as follows: M1 - day 11 at 13.0% parasitemia; M2 - day 10 at 11.1% parasitemia; M3 - day 10 at 18.6% parasitemia; D – day 11 at 18.7% parasitemia. b. Infection #1 (I1), infection #2 (I2), infection #3 (I3), infection #4 (I4) – four groups of mice infected on four separate occasions using P. yoelii 17X iRBCs obtained from four separate donor mice. In each case, P. yoelii 17X RNA was isolated from iRBCs obtained on days 10-11 of infection when parasitemia was ascending and was ~15%. c. Day 10 (D10), Day 14 (D14) – P. yoelii 17X RNA isolated from iRBCs during infection #2 on day 10 (14% parasitemia, 14.4% reticulocytes) and on day 14 of infection #2 (43.5% parasitemia, 57.9% reticulocytes). d. WT and JHD - P. yoelii 17X RNA isolated from iRBCs during infection #4 from immunologically intact, wild-type Balb/c mice and B cell deficient, JHD mice on a Balb/c background (ascending infection, 15% parasitemia). e. QA and RMP - P. yoelii 17X RNA isolated from iRBCs during infection #1 from mice previously immunized with a preparation of membrane proteins isolated from P. yoelii 17X infected reticulocytes (PyRMP) (day 12, 13.3% parasitemia and Quil A immunized (QA) control mice (day 10, 15.6% parasitemia) 2. On each array, gene expression in P. yoelii 17X blood-stage parasites was evaluated relative to a standard comparator of purified P. yoelii 17XL total RNA (pooled RNA from 45 mice, mean parasitemia ~35%). Each sample was analyzed on three replicate arrays, one of which was a standard dye-flip. One exception was the infection #3 sample which was analyzed on only on two arrays. On each array, oligonucleotides were spotted in duplicate. 3. Through the use of the standard reference RNA, the following 15 pairwise comparisons across samples were made: (M1 vs M2); (M2 vs M3); (M1 vs M3); (D vs M1); (D vs M2); (D vs M3); (I1 vs I2); (I1 vs I3); (I1 vs I4); (I2 vs I3); (I2 vs I4); (I3 vs I4); (D10 vs D14); (WT vs JHD); (QA vs RMP)

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Differential immune response associated to malaria outcome is detectable in peripheral blood following Plasmodium yoelii infection in mice.

Publications

Differential immune response associated to malaria outcome is detectable in peripheral blood following Plasmodium yoelii infection in mice.

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