Faculty Opinions recommendation of Dendritic cells induce immunity and long-lasting protection against blood-stage malaria despite an in vitro parasite-induced maturation defect.

2004 ◽  
Author(s):  
Christian Engwerda
Keyword(s):  
Dendritic Cells ◽  
Blood Stage ◽  
Maturation Defect ◽  
Blood Stage Malaria

scholarly journals Dendritic Cells Induce Immunity and Long-Lasting Protection against Blood-Stage Malaria despite an In Vitro Parasite-Induced Maturation Defect

2004 ◽  
Vol 72 (9) ◽  
pp. 5331-5339 ◽  
Author(s):  
Dodie S. Pouniotis ◽  
Owen Proudfoot ◽  
Violeta Bogdanoska ◽  
Vasso Apostolopoulos ◽  
Theodora Fifis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Maturation Defect ◽  
Blood Stage Malaria

ABSTRACT Dendritic cells (DC) suffer a maturation defect following interaction with erythrocytes infected with malaria parasites and become unable to induce protective malaria liver-stage immunity. Here we show that, by contrast, maturation-arrested DC in vitro are capable of the successful induction of antigen-specific gamma interferon (IFN-γ) and interleukin 4 (IL-4) T-cell responses, antibody responses, and potent protection against lethal blood-stage malaria challenge in vivo. Similar results were found with DC pulsed with intact parasitized Plasmodium yoelii or Plasmodium chabaudi erythrocytes. Cross-strain protection was also induced. High levels of protection (80 to 100%) against lethal challenge were evident from 10 days after a single immunization and maintained up to 120 days. Interestingly, correlation studies versus blood-stage protection at different time points suggest that the immune effector mechanisms associated with protection could change over time. Antibody-independent, T-cell- and IL-12-associated protection was observed early after immunization, followed by antibody and IL-4-associated, IFN-γ-independent protection in long-term studies. These results indicate that DC, even when clearly susceptible to parasite-induced maturation defect effects in vitro, can be central to the induction of protection against blood-stage malaria in vivo.

scholarly journals Osteoclasts Are Required for Hematopoietic Stem and Progenitor Cell Mobilization but Not for Stress Erythropoiesis inPlasmodium chabaudi adamiMurine Malaria

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Hugo Roméro ◽  
Christopher Warburton ◽  
Jaime Sanchez-Dardon ◽  
Tatiana Scorza
Keyword(s):  
Bone Marrow ◽  
Hematological Parameters ◽  
Blood Stage ◽  
Hematopoietic Stem ◽  
Stress Erythropoiesis ◽  
Splenic Macrophages ◽  
Stem And Progenitor Cells ◽  
Cell Mobilization ◽  
Blood Stage Malaria

The anemia and inflammation concurrent with blood stage malaria trigger stress haematopoiesis and erythropoiesis. The activity of osteoclasts seems required for the mobilization of hematopoietic stem and progenitor cells (HSPC) from the bone marrow to the periphery. Knowing that BALB/c mice with acutePlasmodium chabaudi adamimalaria have profound alterations in bone remodelling cells, we evaluated the extent to which osteoclasts influence their hematopoietic response to infection. For this, mice were treated with osteoclast inhibiting hormone calcitonin prior to parasite inoculation, and infection as well as hematological parameters was studied. In agreement with osteoclast-dependent HSPC mobilization, administration of calcitonin led to milder splenomegaly, reduced numbers of HSPC in the spleen, and their retention in the bone marrow. Although C-terminal telopeptide (CTX) levels, indicative of bone resorption, were lower in calcitonin-treated infected mice, they remained comparable in naive and control infected mice. Calcitonin-treated infected mice conveniently responded to anemia but generated less numbers of splenic macrophages and suffered from exacerbated infection; interestingly, calcitonin also decreased the number of macrophages generatedin vitro. Globally, our results indicate that although osteoclast-dependent HSC mobilization from bone marrow to spleen is triggered in murine blood stage malaria, this activity is not essential for stress erythropoiesis.

scholarly journals Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Author(s):  
Stephen Derek Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
Parasite Multiplication ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.Methods The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and <0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 hours (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI: 18.5 – 64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI: 8.5 – 15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI: 3.61 – 4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI: 4.16 – 4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration Australian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

scholarly journals Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Stephen D. Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey A. Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
In Vitro Expansion ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134

scholarly journals Development of a Novel CD4+TCR Transgenic Line That Reveals a Dominant Role for CD8+Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria

2017 ◽  
Vol 199 (12) ◽  
pp. 4165-4179 ◽  
Author(s):  
Daniel Fernandez-Ruiz ◽  
Lei Shong Lau ◽  
Nazanin Ghazanfari ◽  
Claerwen M. Jones ◽  
Wei Yi Ng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Transgenic Line ◽  
Dominant Role ◽  
Blood Stage ◽  
Blood Stage Malaria ◽  
Ctl Responses

Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5522-5531 ◽  
Author(s):  
Anne-Marit Sponaas ◽  
Ana Paula Freitas do Rosario ◽  
Cecile Voisine ◽  
Beatris Mastelic ◽  
Joanne Thompson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Defense Mechanism ◽  
Merozoite Surface Protein ◽  
Acute Stage ◽  
Blood Stage ◽  
Oxygen Intermediates ◽  
Blood Stage Malaria

AbstractHost responses controlling blood-stage malaria include both innate and acquired immune effector mechanisms. During Plasmodium chabaudi infection in mice, a population of CD11bhighLy6C+ monocytes are generated in bone marrow, most of which depend on the chemokine receptor CCR2 for migration from bone marrow to the spleen. In the absence of this receptor mice harbor higher parasitemias. Most importantly, splenic CD11bhighLy6C+ cells from P chabaudi–infected wild-type mice significantly reduce acute-stage parasitemia in CCR2−/− mice. The CD11bhighLy6C+ cells in this malaria infection display effector functions such as production of inducible nitric oxide synthase and reactive oxygen intermediates, and phagocytose P chabaudi parasites in vitro, and in a proportion of the cells, in vivo in the spleen, suggesting possible mechanisms of parasite killing. In contrast to monocyte-derived dendritic cells, CD11bhighLy6C+ cells isolated from malaria-infected mice express low levels of major histocompatibility complex II and have limited ability to present the P chabaudi antigen, merozoite surface protein-1, to specific T-cell receptor transgenic CD4 T cells and fail to activate these T cells. We propose that these monocytes, which are rapidly produced in the bone marrow as part of the early defense mechanism against invading pathogens, are important for controlling blood-stage malaria parasites.

scholarly journals Impairment of Protective Immunity to Blood-Stage Malaria by Concurrent Nematode Infection

2005 ◽  
Vol 73 (6) ◽  
pp. 3531-3539 ◽  
Author(s):  
Zhong Su ◽  
Mariela Segura ◽  
Kenneth Morgan ◽  
J. Concepcion Loredo-Osti ◽  
Mary M. Stevenson
Keyword(s):  
Transforming Growth Factor ◽  
Gastrointestinal Nematode ◽  
Interleukin 10 ◽  
Nematode Infection ◽  
Blood Stage ◽  
Ifn Γ ◽  
Tgf Β1 ◽  
Blood Stage Malaria

ABSTRACT Helminthiases, which are highly prevalent in areas where malaria is endemic, have been shown to modulate or suppress the immune response to unrelated antigens or pathogens. In this study, we established a murine model of coinfection with a gastrointestinal nematode parasite, Heligmosomoides polygyrus, and the blood-stage malaria parasite Plasmodium chabaudi AS in order to investigate the modulation of antimalarial immunity by concurrent nematode infection. Chronic infection with the nematode for 2, 3, or 5 weeks before P. chabaudi AS infection severely impaired the ability of C57BL/6 mice to control malaria, as demonstrated by severe mortality and significantly increased malaria peak parasitemia levels. Coinfected mice produced significantly lower levels of gamma interferon (IFN-γ) during P. chabaudi AS infection than mice infected with malaria alone. Concurrent nematode infection also suppressed production of type 1-associated, malaria-specific immunoglobulin G2a. Mice either infected with the nematode alone or coinfected with the nematode and malaria had high transforming growth factor β1 (TGF-β1) levels, and concurrent nematode and malaria infections resulted in high levels of interleukin-10 in vivo. Splenic CD11c+ dendritic cells (DC) from mice infected with malaria alone and coinfected mice showed similarly increased expression of CD40, CD80, and CD86, but DC from coinfected mice were unable to induce CD4+ T-cell proliferation and optimal IFN-γ production in response to the malaria antigen in vitro. Importantly, treatment of nematode-infected mice with an anthelmintic drug prior to malaria infection fully restored protective antimalarial immunity and reduced TGF-β1 levels. These results demonstrate that concurrent nematode infection strongly modulates multiple aspects of immunity to blood-stage malaria and consequently impairs the development of protective antimalarial immunity.

scholarly journals Identification and Immune Assessment of T Cell Epitopes in Five Plasmodium falciparum Blood Stage Antigens to Facilitate Vaccine Candidate Selection and Optimization

2021 ◽  
Vol 12 ◽  
Author(s):  
Vinayaka Kotraiah ◽  
Timothy W. Phares ◽  
Frances E. Terry ◽  
Pooja Hindocha ◽  
Sarah E. Silk ◽  
...  
Keyword(s):  
T Cell ◽  
In Silico ◽  
Malaria Vaccine ◽  
Ex Vivo ◽  
Class Ii ◽  
Blood Stage ◽  
Hla Dr ◽  
Ifn Γ ◽  
Blood Stage Malaria

The hurdles to effective blood stage malaria vaccine design include immune evasion tactics used by the parasite such as redundant invasion pathways and antigen variation among circulating parasite strains. While blood stage malaria vaccine development primarily focuses on eliciting optimal humoral responses capable of blocking erythrocyte invasion, clinically-tested Plasmodium falciparum (Pf) vaccines have not elicited sterile protection, in part due to the dramatically high levels of antibody needed. Recent development efforts with non-redundant, conserved blood stage antigens suggest both high antibody titer and rapid antibody binding kinetics are important efficacy factors. Based on the central role of helper CD4 T cells in development of strong, protective immune responses, we systematically analyzed the class II epitope content in five leading Pf blood stage antigens (RH5, CyRPA, RIPR, AMA1 and EBA175) using in silico, in vitro, and ex vivo methodologies. We employed in silico T cell epitope analysis to enable identification of 67 HLA-restricted class II epitope clusters predicted to bind a panel of nine HLA-DRB1 alleles. We assessed a subset of these for HLA-DRB1 allele binding in vitro, to verify the in silico predictions. All clusters assessed (40 clusters represented by 46 peptides) bound at least two HLA-DR alleles in vitro. The overall epitope prediction to in vitro HLA-DRB1 allele binding accuracy was 71%. Utilizing the set of RH5 class II epitope clusters (10 clusters represented by 12 peptides), we assessed stimulation of T cells collected from HLA-matched RH5 vaccinees using an IFN-γ T cell recall assay. All clusters demonstrated positive recall responses, with the highest responses – by percentage of responders and response magnitude – associated with clusters located in the N-terminal region of RH5. Finally, a statistically significant correlation between in silico epitope predictions and ex vivo IFN-γ recall response was found when accounting for HLA-DR matches between the epitope predictions and donor HLA phenotypes. This is the first comprehensive analysis of class II epitope content in RH5, CyRPA, RIPR, AMA1 and EBA175 accompanied by in vitro HLA binding validation for all five proteins and ex vivo T cell response confirmation for RH5.

scholarly journals Development and evaluation of a new P. falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Author(s):  
Stephen Derek Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
Parasite Multiplication ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New antimalarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating antimalarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. We aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.Methods We expanded the 3D7-V2 MCB in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and <0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable Plasmodium falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 hours (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI: 18.5 – 64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI: 8.5 – 15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI: 3.61 – 4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI: 4.16 – 4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies.Trial Registration Australian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

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