scholarly journals A transient resistance to blood-stage malaria in interferon-γ-deficient mice through impaired production of the host cells preferred by malaria parasites

2015 ◽  
Vol 6 ◽  
Author(s):  
Hiroko Okada ◽  
Kazutomo Suzue ◽  
Takashi Imai ◽  
Tomoyo Taniguchi ◽  
Chikako Shimokawa ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Blood Stage ◽  
Host Cells ◽  
Malaria Parasites ◽  
Deficient Mice ◽  
Blood Stage Malaria

Characterization of a Plasmodium falciparum PHISTc protein, PF3D7_0801000, in blood- stage malaria parasites

2021 ◽  
Vol 80 ◽  
pp. 102240
Author(s):  
Hikaru Nagaoka ◽  
Bernard N. Kanoi ◽  
Masayuki Morita ◽  
Takahiro Nakata ◽  
Nirianne M.Q. Palacpac ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Stage ◽  
Malaria Parasites ◽  
Blood Stage Malaria

Parasite killing in murine malaria does not require nitric oxide production

Parasitology ◽  
1999 ◽  
Vol 118 (2) ◽  
pp. 139-143 ◽  
Author(s):  
N. FAVRE ◽  
B. RYFFEL ◽  
W. RUDIN
Keyword(s):  
Nitric Oxide ◽  
Blood Stage ◽  
No Production ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Deficient Mice ◽  
Stage Parasite ◽  
Blood Stage Malaria ◽  
Inducible Nitric Oxide

Nitric oxide (NO) production has been suggested to play a role as effector molecule in the control of the malarial infections. However, the roles of this molecule are debated. To assess whether blood-stage parasite killing is NO dependent, we investigated the course of blood-stage Plasmodium chabaudi chabaudi (Pcc) infections in inducible nitric oxide synthase (iNOS)-deficient mice. Parasitaemia, haematological alterations, and survival were not affected by the lack of iNOS. To exclude a role of NO produced by other NOS, controls included NO suppression by oral administration of aminoguanidine (AG), a NOS inhibitor. As in iNOS-deficient mice, no difference in the parasitaemia course, survival and haematological values was observed after AG treatment. Our results indicate that NO production is not required for protection against malaria in our murine experimental model. However, C57BL/6 mice treated with AG lost their resistance to Pcc infections, suggesting that the requirement for NO production for parasite killing in murine blood-stage malaria might be strain dependent.

scholarly journals Guided STED nanoscopy enables super-resolution imaging of blood stage malaria parasites

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jan-Gero Schloetel ◽  
Jörn Heine ◽  
Alan F. Cowman ◽  
Michał Pasternak
Keyword(s):  
Super Resolution ◽  
Blood Stage ◽  
Malaria Parasites ◽  
Resolution Imaging ◽  
Blood Stage Malaria

scholarly journals An essential amino acid synchronises malaria parasite development with daily host rhythms

2020 ◽  
Author(s):  
Kimberley F. Prior ◽  
Benita Middleton ◽  
Alíz T.Y. Owolabi ◽  
Mary L. Westwood ◽  
Jacob Holland ◽  
...  
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Blood Stage ◽  
Parasite Development ◽  
Host Feeding ◽  
Malaria Parasites ◽  
Disease Symptoms ◽  
Development Cycle ◽  
Feeding Rhythms ◽  
Blood Stage Malaria

SummaryThe replication of blood-stage malaria parasites is synchronised to the host’s daily feeding rhythm. We demonstrate that a metabolite provided to the parasite from the host’s food can set the schedule for Plasmodium chabaudi’s intraerythrocytic development cycle (IDC). First, a large-scale screen reveals multiple rhythmic metabolites in the blood that match the timing of the IDC, but only one - the amino acid isoleucine - that malaria parasites must scavenge from host food. Second, perturbing the timing of isoleucine provision and withdrawal demonstrate that parasites use isoleucine to schedule and synchronise their replication. Thus, periodicity in the concentration of isoleucine in the blood, driven by host-feeding rhythms, explains why timing is beneficial to the parasite and how it coordinates with host rhythms. Blood-stage replication of malaria parasites is responsible for the severity of disease symptoms and fuels transmission; disrupting metabolite-sensing by parasites offers a novel intervention to reduce parasite fitness.

scholarly journals Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

2020 ◽  
Author(s):  
Jian Huang ◽  
Yafei Yuan ◽  
Na Zhao ◽  
Debing Pu ◽  
Qingxuan Tang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Rational Design ◽  
Glucose Transporter ◽  
Blood Stage ◽  
Host Cells ◽  
Sugar Uptake ◽  
Hexose Transporter ◽  
Next Generation ◽  
Malaria Parasites ◽  
Glucose Transporter 1

AbstractArtemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

scholarly journals Vaccination accelerates hepatic erythroblastosis induced by blood-stage malaria

2019 ◽  
Author(s):  
Denis Delic ◽  
Frank Wunderlich ◽  
Saleh Al-Quraishy ◽  
Abdel-Azeem Abdel-Baki ◽  
Mohamed Dkhil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Stage ◽  
Host Cells ◽  
Hepatic Expression ◽  
Gene Expression Microarrays ◽  
Expression Microarrays ◽  
Final Survival ◽  
Blood Stage Malaria ◽  
Maximal Expression ◽  
Lethal Blood

Abstract Background: Vaccination induces survival of otherwise lethal blood-stage infections of the experimental malaria Plasmodium chabaudi. Blood-stage malaria induces extramedullary erythropoiesis in the liver. This study investigates how vaccination affects the course of malaria-induced expression of erythrocytic genes in the liver. Methods: Female Balb/c mice were vaccinated at week 3 and week 1 before challenging with 106 P. chabaudi-parasitized erythrocytes. The non-infectious vaccine consisted of erythrocyte ghosts isolated from P. chabaudi-infected erythrocytes. Gene expression microarrays and quantitative real-time PCR were used to compare mRNA expression of different erythrocytic genes in the liver of vaccination-protected and non-protected mice during infections on days 0, 1, 4, 8, and 11 p.i.. Results: Global transcriptomics analyses reveal vaccination-induced modifications of malaria-induced increases in hepatic gene expression on days 4 and 11 p.i.. On these days, vaccination also alters hepatic expression of the erythropoiesis-involved genes Ermap, Kel, Rhd, Rhag, Slc4a1, Gypa, Add2, Ank1, Epb4.1, Epb4.2, Epb4.9, Spta1, Sptb, Tmod1, Ahsp, Acyp1, Gata1, Gfi1b, Tal1, Klf1, Epor, and Cldn13. In vaccination-protected mice, expression of these genes, except Epb4.1, is significantly higher on day 4 p.i. than in un-protected non-vaccinated mice, reaches maximal expression at peak parasitaemia on day 8 p.i., and is slowed down or even decreased towards the end of crisis phase on day 11 p.i.. After day 1 p.i., Epor expression takes about the same course as that of the other erythroid genes. Hepatic expression of Epo, however, is delayed in both vaccinated and non-vaccinated mice for the first 4 days p.i. and is maximal at significantly higher levels in vaccinated mice on day 8 p.i., before declining towards the end of crisis phase on day 11 p.i.. Conclusion: The present data indicate that vaccination accelerates malaria-induced erythroblastosis in the liver for 1-2 days. This may contribute to earlier replenishment of peripheral red blood cells by liver-derived reticulocytes, which may favour final survival of otherwise lethal blood-stage malaria, since reticulocytes are not preferred as host cells by P. chabaudi.

scholarly journals Vaccination accelerates hepatic erythroblastosis induced by blood-stage malaria

2020 ◽  
Author(s):  
Denis Delic ◽  
Frank Wunderlich ◽  
Saleh Al-Quraishy ◽  
Abdel-Azeem S. Abdel-Baki ◽  
Mohamed A. Dkhil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Stage ◽  
Host Cells ◽  
Hepatic Expression ◽  
Gene Expression Microarrays ◽  
Expression Microarrays ◽  
Final Survival ◽  
Blood Stage Malaria ◽  
Maximal Expression ◽  
Lethal Blood

Abstract Background Vaccination induces survival of otherwise lethal blood-stage infections of the experimental malaria Plasmodium chabaudi . Blood-stage malaria induces extramedullary erythropoiesis in the liver. This study investigates how vaccination affects the course of malaria-induced expression of erythrocytic genes in the liver. Methods Female Balb/c mice were vaccinated at week 3 and week 1 before challenging with 10 6 P. chabaudi- parasitized erythrocytes. The non-infectious vaccine consisted of erythrocyte ghosts isolated from P. chabaudi -infected erythrocytes. Gene expression microarrays and quantitative real-time PCR were used to compare mRNA expression of different erythrocytic genes in the liver of vaccination-protected and non-protected mice during infections on days 0, 1, 4, 8, and 11 p.i. . Results Global transcriptomics analyses reveal vaccination-induced modifications of malaria-induced increases in hepatic gene expression on days 4 and 11 p.i.. On these days, vaccination also alters hepatic expression of the erythropoiesis-involved genes Ermap, Kel, Rhd , Rhag , Slc4a1, Gypa, Add2, Ank1, Epb4.1, Epb4.2, Epb4.9, Spta1, Sptb, Tmod1 , Ahsp, Acyp1 , Gata1, Gfi1b, Tal1, Klf1, Epor , and Cldn13 . In vaccination-protected mice, expression of these genes, except Epb4.1 , is significantly higher on day 4 p.i. than in un-protected non-vaccinated mice, reaches maximal expression at peak parasitaemia on day 8 p.i., and is slowed down or even decreased towards the end of crisis phase on day 11 p.i.. After day 1 p.i., Epor expression takes about the same course as that of the other erythroid genes. Hepatic expression of Epo, however, is delayed in both vaccinated and non-vaccinated mice for the first 4 days p.i. and is maximal at significantly higher levels in vaccinated mice on day 8 p.i. , before declining towards the end of crisis phase on day 11 p.i. . Conclusion The present data indicate that vaccination accelerates malaria-induced erythroblastosis in the liver for 1-2 days. This may contribute to earlier replenishment of peripheral red blood cells by liver-derived reticulocytes, which may favour final survival of otherwise lethal blood-stage malaria, since reticulocytes are not preferred as host cells by P. chabaudi .

scholarly journals Blood-stage malaria parasites manipulate host innate immune responses through the induction of sFGL2

2020 ◽  
Vol 6 (9) ◽  
pp. eaay9269
Author(s):  
Yong Fu ◽  
Yan Ding ◽  
Qinghui Wang ◽  
Feng Zhu ◽  
Yulong Tan ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Natural Killer ◽  
Underlying Mechanism ◽  
Innate Immune ◽  
Blood Stage ◽  
Innate Immune Responses ◽  
Malaria Parasites ◽  
Monocyte Chemoattractant Protein 1 ◽  
Blood Stage Malaria

Malaria parasites suppress host immune responses to facilitate their survival, but the underlying mechanism remains elusive. Here, we found that blood-stage malaria parasites predominantly induced CD4+Foxp3+CD25+ regulatory T cells to release soluble fibrinogen-like protein 2 (sFGL2), which substantially enhanced the infection. This was attributed to the capacity of sFGL2 to inhibit macrophages from releasing monocyte chemoattractant protein-1 (MCP-1) and to sequentially reduce the recruitment of natural killer/natural killer T cells to the spleen and the production of interferon-γ. sFGL2 inhibited c-Jun N-terminal kinase phosphorylation in the Toll-like receptor 2 signaling pathway of macrophages dependent on FcγRIIB receptor to release MCP-1. Notably, sFGL2 were markedly elevated in the sera of patients with malaria, and recombinant FGL2 substantially suppressed Plasmodium falciparum from inducing macrophages to release MCP-1. Therefore, we highlight a previously unrecognized immune suppression strategy of malaria parasites and uncover the fundamental mechanism of sFGL2 to suppress host innate immune responses.

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