Malaria Hidden in a Patient with Diffuse Large-B-Cell Lymphoma and Sickle-Cell Trait

Camacho

et al. 2013

British J Pharmacology

BACKGROUND AND PURPOSEBlood-stage Plasmodium parasites cause morbidity and mortality from malaria. Parasite resistance to drugs makes development of new chemotherapies an urgency. Aminoacyl-tRNA synthetases have been validated as antimalarial drug targets. We explored long-term effects of borrelidin and mupirocin in lethal P. yoelii murine malaria. EXPERIMENTAL APPROACHLong-term (up to 340 days) immunological responses to borrelidin or mupirocin were measured after an initial 4 day suppressive test. Prophylaxis and cure were evaluated and the inhibitory effect on the parasites analysed. KEY RESULTSBorrelidin protected against lethal malaria at 0.25 mg·kg. Antimalarial activity of borrelidin correlated with accumulation of trophozoites in peripheral blood. All infected mice treated with borrelidin survived and subsequently developed immunity protecting them from re-infection on further challenges, 75 and 340 days after the initial infection. This long-term immunity in borrelidin-treated mice resulted in negligible parasitaemia after re-infections and marked increases in total serum levels of antiparasite IgGs with augmented avidity. Long-term memory IgGs mainly reacted against high and low molecular weight parasite antigens. Immunofluorescence microscopy showed that circulating IgGs bound predominantly to late intracellular stage parasites, mainly schizonts. CONCLUSIONS AND IMPLICATIONSLow borrelidin doses protected mice from lethal malaria infections and induced protective immune responses after treatment. Development of combination therapies with borrelidin and selective modifications of the borrelidin molecule to specifically inhibit plasmodial threonyl tRNA synthetase should improve therapeutic strategies for malaria. AbbreviationsARS, aminoacyl-tRNA synthetases; IleRS, isoleucyl t-RNA synthetase; NAI, naturally acquired immunity; pi, post-infection; Py17XL, P. yoelii 17XL; ThrRS, threonyl t-RNA synthetase

Section: Discussionmentioning

confidence: 97%

Insights into the preclinical treatment of blood‐stage malaria by the antibiotic borrelidin

Camacho

et al. 2013

British J Pharmacology

“…In the second trial, the humoral response developed by BALB/c mice after the four vaccination challenges was characterized by immunoblot which confirmed the immunogenicity of our isolated antigens. A large variety of PyL specific IgGs were developed against a wide range of parasite proteins, similar to the build-up of the humoral response observed in partially immunized humans [ 51 ]. The key role of B cells in controlling malaria infections has been clearly revealed in rodent models lacking these cells, which are not able to eliminate P. yoelii [ 35 ] and P. chabaudi infections [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Experimental Immunization Based onPlasmodiumAntigens Isolated by Antibody Affinity

Kamali

Journal of Immunology Research

et al. 2015

Self Cite

Vaccines blocking malaria parasites in the blood-stage diminish mortality and morbidity caused by the disease. Here, we isolated antigens from total parasite proteins by antibody affinity chromatography to test an immunization against lethal malaria infection in a murine model. We used the sera of malaria self-resistant ICR mice to lethal Plasmodium yoelii yoelii 17XL for purification of their IgGs which were subsequently employed to isolate blood-stage parasite antigens that were inoculated to immunize BALB/c mice. The presence of specific antibodies in vaccinated mice serum was studied by immunoblot analysis at different days after vaccination and showed an intensive immune response to a wide range of antigens with molecular weight ranging between 22 and 250 kDa. The humoral response allowed delay of the infection after the inoculation to high lethal doses of P. yoelii yoelii 17XL resulting in a partial protection against malaria disease, although final survival was managed in a low proportion of challenged mice. This approach shows the potential to prevent malaria disease with a set of antigens isolated from blood-stage parasites.

“…Protein extracts from in vitro cultures of Plasmodium falciparum. Clinical P. falciparum isolate UCM7 31 from West Africa was cultured to high parasitemia (>50%) following the previously described method 55 . Briefly, the culture media consisted of standard RPMI 1640 (Sigma-Aldrich) supplemented with 0.5% Albumax I (Gibco), 100 μM Hypoxanthine (Sigma-Aldrich), 25 mM 101 HEPES (Sigma-Aldrich), 12.5 μg/mL Gentamicine (Sigma-Aldrich) and 25 mM NaHCO 3 (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…To further identify differential IgG reactive antigens, detailed immunoproteomics was performed. Thus, the total P. falciparum intraerythrocytic proteome obtained in 2D-PAGE from a clinical isolate, originally causing subclinical malaria 31 , showed 862 ± 14 spots within the range at 3-11 isoelectric point and 3-260 kDa molecular weight ( Figure S2). The corresponding 2D immunoblots using sera from imported malaria cases revealed different immunoreactivity patterns for each group of patients ( Figure S2).…”

Section: Immunoproteomics Of P Falciparum Blood Stage Antigens the mentioning

confidence: 99%

Plasmodium falciparum immunodominant IgG epitopes in subclinical malaria

Abad

et al. 2020

Sci Rep

Self Cite

incomplete non-sterile immunity to malaria is attained in endemic regions after recurrent infections by a large percentage of the adult population, who carry the malaria parasite asymptomatically. Although blood-stage Plasmodium falciparum rapidly elicits IgG responses, the target antigens of partially protective and non-protective IgG antibodies as well as the basis for the acquisition of these antibodies remain largely unknown. We performed IgG-immunomics to screen for P. falciparum antigens and to identify epitopes associated with exposure and clinical disease. Sera from malaria cases identified five prevalent antigens recognized by all analyzed patients' IgGs. Epitope mapping of them, using adult and children sera samples from an endemic malaria region in Ghana segregated into patients with positive or negative subclinical detection of P. falciparum, revealed binding specificity for two 20-mer immunodominant antigenic regions within the START-related lipid transfer protein and the protein disulfide isomerase PDI8. These 20-mer epitopes challenged with sera samples from children under 5 years old displayed specific IgG binding in those with detectable parasitemia, even at subclinical level. These results suggest that humoral response against START and PDI8 antigens may be triggered at submicroscopic parasitemia levels in children and may eventually be used to differentially diagnose subclinical malaria in children. Endemic Plasmodium falciparum malaria causes million clinical cases and hundreds of thousand deaths worldwide 1 , although the global disease toll probably exceed these numbers 2,3. Most deaths occur in sub-Saharan Africa (90%) and in children under 5 years old (70%) 1. In non-endemic areas, malaria could also be a public health threat due to international tourism and migration to and from endemic areas, which has led to the occasional re-emergence of this parasitic disease as imported infection 4. In-housing vector control, elementary clinical diagnosis and therapeutic drugs are the only available management strategy for both malaria prevention and treatment in endemic regions. As a necessary step towards malaria elimination neither vaccine nor diagnostics of subclinical reservoirs are widely available. After repeated exposure to the parasite, those who survive malaria early in life eventually acquire resistance to the disease 5 , but the mechanisms that underlie this immunity remain poorly understood 6. Landmark studies in the 1960s showed that purified IgG from malaria-immune adults transferred to acute-malaria infected children leads to reduction of both fever and parasitemia 7 , thus indicating that antibodies against P. falciparum proteins play a critical role in controlling the blood stage of the infection. However, it is still unknown which of the 5,300 proteins presently annotated in the P. falciparum genome (PlasmoDB, www.plasmodb.org) elicit the production of protective antibodies 8. In addition to allelic variations of MHC molecules, the degree of antigen exposure, antigen abundance and ...