Vaccination accelerates hepatic erythroblastosis induced by blood-stage malaria

Delić, Denis; Wunderlich, Frank; Al‐Quraishy, Saleh; Abdel‐Baki, Abdel‐Azeem S.; Dkhil, Mohamed A.; Araúzo‐Bravo, Marcos J.

doi:10.1186/s12936-020-3130-2

Cited by 12 publications

(26 citation statements)

References 57 publications

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“…Many of these RBC disorder genes have been associated with malaria response in mice or humans. For instance, in mice vaccinated with erythrocyte ghosts isolated from P. chaubaudi -infected erythrocytes, RHAG , SPTA1 , KLF1 , and SLC4A1 were among the erythropoiesis-involved genes that were significantly upregulated in response to infection with blood stage Plasmodium chabaudi (Delic et al, 2020). Furthermore, variation in SPTA1 , which encodes a component of the RBC plasma membrane, was recently found to impact P. falciparum growth in cultured human RBCs (Ebel et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Immunogenetic response to a malaria-like parasite in a wild primate

Bergey

2020

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Malaria is infamous for the massive toll it exacts on human life and health. In the face of this intense selection, many human populations have evolved mechanisms that confer some resistance to the disease, such as sickle-cell hemoglobin or the Duffy null blood group. Less understood are adaptations in other vertebrate hosts, many of which have a longer history of co-evolution with malaria parasites. By comparing malaria resistance adaptations across host species, we can gain fundamental insight into host-parasite co-evolution. In particular, understanding the mechanisms by which non-human primate immune systems combat malaria may be fruitful in uncovering transferable therapeutic targets for humans. However, most research on primate response to malaria has focused on a single or few loci, typically in experimentally-infected captive primates. Here, we report the first transcriptomic study of a wild primate response to a malaria-like parasite, investigating gene expression response of red colobus monkeys (Piliocolobus tephrosceles) to natural infection with the malaria-like parasite, Hepatocystis. We identified colobus genes with expression strongly correlated with parasitemia, including many implicated in human malaria and suggestive of common genetic architecture of disease response. For instance, the expression of ACKR1 (alias DARC) gene, previously linked to resistance in humans, was found to be positively correlated with parasitemia. Other similarities to human parasite response include induction of changes in immune cell type composition and, potentially, increased extramedullary hematopoiesis and altered biosynthesis of neutral lipids. Our results illustrate the utility of comparative immunogenetic investigation of malaria response in primates. Such inter-specific comparisons of transcriptional response to pathogens afford a unique opportunity to compare and contrast the adaptive genetic architecture of disease resistance, which may lead to the identification of novel intervention targets to improve human health.Author SummaryThe co-evolutionary arms race between humans and malaria parasites has been ongoing for millennia. Fully understanding the evolved human response to malaria is impossible without comparative study of parasites in our non-human primate relatives. Though laboratory primates are fruitful models, the complexity of wild primates infected in a natural transmission system may be a more suitable comparison for contextualizing malaria infections in human patients. Here, we investigate the genetic mechanisms underlying the immune response to Hepatocystis, a close relative of human-infective malaria, in a population of wild Ugandan red colobus monkeys. We find that the genes involved have considerable overlap with those active in human malaria patients. Like Plasmodium, Hepatocystis induces changes in blood cell type and may cause the host to produce blood components outside of the bone marrow or alter metabolism related to the production of lipids. Our work helps to identify the genetic mechanisms underlying the arms race between primates and malaria parasites, providing fundamental evolutionary insight. Such comparative work on the interaction between wild non-human primates and malaria parasites can identify ways in which primates have evolved resistance to malaria parasites, and further investigation of such implicated genes may lead to novel potential therapeutic and vaccine targets.

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Section: Resultsmentioning

confidence: 99%

Immunogenetic response to a malaria-like parasite in a wild primate

Bergey

2020

Preprint

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“…Mice were vaccinated with a non-infectious vaccine under identical experimental conditions as described elsewhere [ 37 , 44 ]. The vaccine consisted of erythrocyte ghosts isolated from P. chabaudi -parasitized erythrocytes as detailed previously [ 36 , 45 ].…”

Section: Methodsmentioning

confidence: 99%

“…These experiments were also previously performed and their results recently published elsewhere [ 44 ]. In brief, total RNA from aliquots of individual frozen livers “pulverized” under liquid nitrogen was isolated by the standard Trizol protocol (Qiagen, Hilden, Germany) followed by cleaning with the miRNeasy Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…High-Capacity cDNA Reverse Transcription Kit (Life Technologies) and TaqMan mRNA assays (Life Technologies) were used to perform reverse transcription of mRNAs coding for the following proteins: ITGA1 (assay ID: Mm01306375_m1), ITGA2 (assay ID: Mm00434371_m1), KLRG1 (assay ID: Mm00516879_m1), GZMC (assay ID: Mm01313651_m1), GZMN (assay ID: Mm00461851_m1), KLRD1 (assay ID: Mm00495182_m1), KLRB1F (assay ID: Mm04211785_m1), and CLEC2I (assay ID: Mm00777071_g1). PCR reactions were carried out with the TaqMan ® gene expression master mix (Life Technologies) according to the instructions given by the manufacturer on a 7900HT real-time PCR System, as previously described [ 44 ]. Raw Ct values were calculated using the SDS software v.2.4 with GAPDH (assay ID: Mm99999915_g1) for normalization.…”

Section: Methodsmentioning

confidence: 99%

“…Vaccination-induced survival is associated with significantly altered responses of the liver to blood-stage malaria at different phases of infections as shown previously [ 38 , 39 , 40 , 41 , 42 , 43 ]. Most remarkably, vaccination was found to accelerate extramedullary erythroblastosis in the liver induced by blood-stage infections of P. chabaudi [ 44 ]. This has been experimentally evidenced as significantly accelerated expression of erythroid genes in the liver, in particular those genes encoding constituents of erythrocyte surface membranes.…”

Section: Introductionmentioning

confidence: 99%

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Protective Vaccination Reshapes Hepatic Response to Blood-Stage Malaria of Genes Preferentially Expressed by NK Cells

et al. 2020

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The role of natural killer (NK) cells in the liver as first-line post infectionem (p.i.) effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of Plasmodium chabaudi. Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 106P. chabaudi-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 p.i. using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., Itga1 in expanding liver-resident NK (lrNK) cells, Itga2 in immigrating conventional NK (cNK) cells; Eomes and Tbx21 encoding transcription factors; Ncr1, Tnfsf10, Prf1, Gzma, Gzmb, Gzmc, Gzmm, and Gzmk encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs Gzmm expression, accelerates decline of Tnfsf10 and Clec2d expression, whereas it accelerates increased expression of Clec2i, taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 p.i. is highly significantly (p < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of P. chabaudi.

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