A5076889415- Malaria Research and Control
- Mosquito-borne diseases and control
- Research on Leishmaniasis Studies
- Vector-borne infectious diseases
- Complement system in diseases
- Immune Cell Function and Interaction
- HIV Research and Treatment
- Drug Transport and Resistance Mechanisms
- Diabetes and associated disorders
- Computational Drug Discovery Methods
- Advanced Manufacturing and Logistics Optimization
- Parasites and Host Interactions
- Invertebrate Immune Response Mechanisms
- T-cell and B-cell Immunology
- Immunodeficiency and Autoimmune Disorders
- Phenothiazines and Benzothiazines Synthesis and Activities
- Phytochemistry and Bioactivity Studies
- Assembly Line Balancing Optimization
- Hepatitis C virus research
- Extraction and Separation Processes
- Traditional and Medicinal Uses of Annonaceae
- Aquaculture disease management and microbiota
- Chronic Lymphocytic Leukemia Research
- Trypanosoma species research and implications
- Hemoglobinopathies and Related Disorders
Istituto Superiore di Sanità
2015-2024
Technical University of Munich
2021
Sapienza University of Rome
2009-2012
The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified the recent failure first-line therapies across Southeast Asia. Here, we show that trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, chemoproteomic studies, validated conditional knockdown parasites, molecular docking,...
Summary Emerging resistance to first‐line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required protect existing drugs enhance efficacy. We report that piperazine‐containing compound ACT‐451840 exhibits single‐digit nanomolar inhibition of Plasmodium falciparum asexual blood stages transmissible gametocyte forms. Genome sequence analyses in vitro ‐derived ACT‐451840‐resistant parasites revealed single...
New reliable and cost-effective antimalarial drug screening assays are urgently needed to identify drugs acting on different stages of the parasite Plasmodium falciparum, particularly those responsible for human-to-mosquito transmission, that is, P. falciparum gametocytes. Low Z' factors, narrow dynamic ranges, and/or extended assay times commonly reported in current gametocyte measuring gametocyte-expressed fluorescent or luciferase reporters, endogenous ATP levels, activity enzymes,...
Single low-dose primaquine (PQ) reduces Plasmodium falciparum infectivity before it impacts gametocyte density. Here, we examined the effect of PQ on sex ratio as a possible explanation for this early sterilizing effect.
Plasmodium falciparum gametocytes, specifically the mature stages, are only malaria parasite stage in humans transmissible to mosquito vector. Anti-malarial drugs capable of killing these forms considered essential for eradication and tools allowing screening large compound libraries with high predictive power needed identify new candidates. As gametocytes not a replicative it is difficult apply same drug methods used asexual stages. Here we propose an assay, based on content imaging,...
As most available antimalarial drugs are ineffective against the Plasmodium falciparum transmission stages, new parasite's gametocytes urgently needed to combat malaria globally. The unique biology of requires assays that need be specific, faithfully monitor anti-gametocyte activity, and easy perform, cheap scalable high-throughput screening (HTS). We developed an HTS cell-based assay with P. specifically expressing a potent luciferase. To confirm hit activity for several parasite genotypes,...
The egress and fertilization of Plasmodium gametes development a motile ookinete are the first crucial steps that mediate successful transmission malaria parasites from humans to Anopheles vector. However, limited information exists about cell biology regulation this process. Technical impediments in establishment vitro conditions for maturation P. falciparum other human further constrain detailed characterization maturation. Here using fluorescence microscopy immunolabelling, we compared A....
A clonal population of B cells expressing a V H 1‐69‐encoded idiotype accumulates in hepatitis C virus ( HCV ) associated mixed cryoglobulinemia MC ). These are phenotypically heterogeneous, resembling either typical marginal zone MZ I g M + D CD 27 21 or the exhausted low that accumulate HIV infection common variable immunodeficiency. We show both ‐like and 1‐69 patients functionally exhausted, since they fail to respond TLR BCR ligands. The proliferative defect can be overcome by...
The goal to prevent Plasmodium falciparum transmission from humans mosquitoes requires the identification of targetable metabolic processes in mature (stage V) gametocytes, sexual stages circulating bloodstream. This task is complicated by apparently low metabolism these cells, which renders them refractory most antimalarial inhibitors and constrains development specific sensitive cell-based assays. Here, we identify functionally characterize regulatory regions P. gene PF3D7_1234700,...
The presence of Plasmodium falciparum gametocytes in peripheral blood is essential for human to mosquito parasite transmission. detection submicroscopic infections with and the estimation gametocyte sex ratio are crucial assess host potential ability infect mosquitoes transmit malaria parasites. aim this work was develop sensitive cheap Real Time qPCR assays large-scale epidemiological surveys, based on amplification specific transcripts selected from literature: female-specific pfs25 pf...
Abstract To ensure the transport of nutrients necessary for their survival, Plasmodium falciparum parasites increase erythrocyte permeability to diverse solutes. These new permeation pathways (NPPs) have been extensively characterized in pathogenic asexual parasite stages, however existence NPPs has never investigated gametocytes, sexual stages responsible transmission mosquitoes. Here, we show that are still active erythrocytes infected with immature gametocytes and this activity declines...
Abstract Toll‐like receptor 9 (TLR‐9) and TLR‐7 may have a role in the production of anti‐DNA anti‐RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to development systemic lupus erythematosus (SLE). Herein we describe patient with SLE who had long‐lasting remission her autoimmune disease after an antibody deficiency resembling common variable immunodeficiency (CVID). After CVID developed, anti–double‐stranded DNA antibodies disappeared,...
Abstract A subset of patients with common variable immunodeficiency (CVID), group 1a the Freiburg classification, is characterized by increased B cells expressing low levels CD21 (CD21 ), lymphoproliferation and autoimmunity. The have been shown to be profoundly anergic, defects BCR‐mediated calcium signaling T described in CVID 1a. We found that also classical naïve from patients, but not non‐1a proliferated poorly. had a reduced capacity divide reminiscent proliferative arrest associated...
Malaria remains the most important mosquito-borne infectious disease worldwide, with 229 million new cases and 409.000 deaths in 2019. The infection is caused by a protozoan parasite which attacks red blood cells feeding on hemoglobin transforming it into hemozoin. Despite WHO recommendation of prompt malaria diagnosis, quality microscopy-based diagnosis frequently inadequate while rapid diagnostic tests based antigens are not quantitative still affected non-negligible false...
Abstract Blocking Plasmodium falciparum human-to-mosquito transmission is essential for malaria elimination, nonetheless drugs killing the pathogenic asexual stages are generally inactive on parasite transmissible stages, gametocytes. Due to technical and biological limitations in high throughput screening of non-proliferative search gametocyte-killing molecules so far tested one tenth number compounds screened stages. Here we overcome these rapidly around 120,000 compounds, using not...
Novel antimalarial compounds targeting both the pathogenic and transmissible stages of human malaria parasite, Plasmodium falciparum, would greatly benefit elimination strategies. However, most affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact this loss on a compound's transmission-blocking is unclear. Here, we report systematic evaluation gametocytes investigate confounding factors contributing to this. A threshold for acceptable between...
The use of quantitative qRT-PCR assays for detection and quantification late gametocyte stages has revealed the high transmission capacity human malaria parasite, Plasmodium falciparum. To understand how parasite adjusts its in response to in-host environmental conditions including antimalarials requires simultaneous early gametocytes. Here, we describe that specifically detect quantify early-stage P. falciparum are based on expression known genes were developed using purified stage II V...
This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and its newly identified carboxylic acid metabolite on human malaria parasite Plasmodium falciparum. NBDHEX has been previously as a potent cytotoxic agent against murine cancer cells well towards protozoan Giardia duodenalis. We show here that is active in vitro all blood stages P. falciparum, with rare feature killing transmissible to mosquitoes, gametocytes, 4-fold higher potency than...
Recent evidence suggests that the bone marrow (BM) plays a key role in diffusion of P. falciparum malaria by providing "niche" for maturation parasite gametocytes, responsible human-to-mosquito transmission. Suitable humanized vivo models to study mechanisms interplay between and human BM components are still missing. We report novel experimental system based on infusion immature gametocytes into immunocompromised mice carrying chimeric ectopic ossicles whose stromal compartments derive from...