Vascular endothelial growth factor (VEGF) and lovastatin suppress the inflammatory response to<i>Plasmodium berghei</i>infection and protect against experimental cerebral malaria

Canavese, Miriam; Crisanti, Andrea

doi:10.1179/2047773215y.0000000021

Cited by 9 publications

(7 citation statements)

References 30 publications

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“…VEGF, a regulator of endothelial inflammation and integrity, is involved in modulating tissue pathology in response to P. berghei infection. Indeed, a potent inhibitor to the VEGF signaling pathway dramatically aggravated the course of P. berghei infection [45].…”

Section: Discussionmentioning

confidence: 99%

Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria

Nisar

Torres

Thiam

et al. 2022

IJMS

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Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.

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Section: Discussionmentioning

confidence: 99%

Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria

Nisar

Torres

Thiam

et al. 2022

IJMS

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“…VEGF, a regulator of endothelial inflammation and integrity, is involved in modulating tissue pathology in response to P. berghei infection. Indeed, a potent inhibitor to the VEGF signaling pathway aggravated dramatically the course of P. berghei infection 43 .…”

Section: Discussionmentioning

confidence: 99%

Identification of ATP2B4 regulatory element containing functional genetic variants associated with severe malaria

Nisar

Torres

Thiam

et al. 2021

Preprint

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Genome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants that are mostly located in non-coding regions, with only a few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both promoter and enhancer activities and that both individual SNPs and the combination of SNPs had regulatory effects using luciferase reporter assays. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Taken together, our data show that severe malaria-associated genetic variants alter the activity of a promoter with enhancer function. We showed that this regulatory element controls the expression of ATP2B4 that encodes a plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this regulatory element affects the risk of severe malaria probably through calcium concentration effect on parasitaemia.

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“…to investigate the effect of Art-TMP combination in preventing the incidence of ECM at an early stage of malaria infection. Several researchers have initiated empiric novel treatments of ECM administered before, on, or just after the first day of infection for evaluating various effects at different stages of malaria infection [39–43]. Our future studies aim to study the drug effect after 3 to 7 days of infection on long-term prevention of neurological damage in ECM mice.…”

Section: Discussionmentioning

confidence: 99%

Powerful solution for experimental cerebral malaria treatment: artesunate and tetramethylpyrazine

Jiang

Chen

Zheng

et al. 2019

Preprint

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BackgroundCerebral malaria (CM) is a kind of serious neurological complication caused by the acute Plasmodium falciparum infection. About 300000 patients including children under 5 years old died from this disease every year. Even intravenous artesunate (Art) is employed as the most effictive drug in the treatment of CM, high incidence of death and neurological sequelae are still inevitable. Therefore, we assessed the combination of Art and tetramethylpyrazine (TMP), to treat experimental CM (ECM) in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). A non-biased whole brain quantitative proteomic analysis was also conducted to get some insight of the mechanism of the combinational treatment.ResultsTreatment of (ECM)-C57BL/6 mice with the combination of Art and TMP increased the survival, improved clinical signs and prevented neurological manifestations. These effects were related to reduction of parasitised red blood cells (pRBC) adhesion, sequestration, maintaining brain microvascular integrity, increasing nerve growth factor, neurotrophin levels, and alleviating hippocampal neuronal damage and astrocyte activation. The pharmacological effects of Art-TMP combination therapy were analyzed by ECM mice brain proteomic function enrichment. Based on an isobaric tag for relative and absolute quantitation (iTRAQ) fold-change of 1.2 (P-value < 0.05), 217 down-regulated and 177 up-regulated proteins were identified, presenting a significantly altered proteome profile of the combined Art and TMP group as compared to the group treated with Art or TMP alone. These results suggested that the Art-TMP combination could be used as a powerful solution for CM and its neurologic damage.ConclusionsAn effictive therapy for CM with low mortality rate and protect against ECM-induced neurocognitive impairment has been proposed through the combination of Art and TMP, which can provide an effective adjuvant treatment in the clinic. iTRAQ proteomics provide a resource for further mechanistic studies to examine the synergistic effects of Art and TMP and their potential to serve as an adjunctive treatment method and intervention targets.Author SummaryCerebral malaria (CM) is the most serious neurological complication caused by Plasmodium falciparum infection. Even after antimalarial treatment, severe neurological sequelae still exist. We used tetramethylpyrazine (TMP), the main ingredient of the traditional Chinese medicine Chuanxiong, and artesunate (Art) as a combination of drugs. We found that Art-TMP combination could improve the clinical symptoms of CM and protect the nervous system. At the same time, proteomics was used to analyze the protective mechanism of Art-TMP combination administration on ECM mice. This study suggests that the combination of Art and TMP may be used as an adjuvant therapy for clinical CM and iTRAQ proteomics provides resources for further study of Art-TMP combination and provides potential prognostic biomarkers for this therapeutic intervention.

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Vascular endothelial growth factor (VEGF) and lovastatin suppress the inflammatory response toPlasmodium bergheiinfection and protect against experimental cerebral malaria

Cited by 9 publications

References 30 publications

Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria

Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria

Identification of ATP2B4 regulatory element containing functional genetic variants associated with severe malaria

Powerful solution for experimental cerebral malaria treatment: artesunate and tetramethylpyrazine

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