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Profile of metacaspase gene expression in Plasmodium vivax field isolates from the Brazilian Amazon.Molecular Biology Reports Apr 2024Metacaspases comprise a family of cysteine proteases implicated in both cell death and cell differentiation of protists that has been considered a potential drug target...
BACKGROUND
Metacaspases comprise a family of cysteine proteases implicated in both cell death and cell differentiation of protists that has been considered a potential drug target for protozoan parasites. However, the biology of metacaspases in Plasmodium vivax - the second most prevalent and most widespread human malaria parasite worldwide, whose occurrence of chemoresistance has been reported in many endemic countries, remains largely unexplored. Therefore, the present study aimed to address, for the first time, the expression pattern of metacaspases in P. vivax parasites.
METHODS AND RESULTS
P. vivax blood-stage parasites were obtained from malaria patients in the Brazilian Amazon and the expression of the three putative P. vivax metacaspases (PvMCA1-3) was detected in all isolates by quantitative PCR assay. Of note, the expression levels of each PvMCA varied noticeably across isolates, which presented different frequencies of parasite forms, supporting that PvMCAs may be expressed in a stage-specific manner as previously shown in P. falciparum.
CONCLUSION
The detection of metacaspases in P. vivax blood-stage parasites reported herein, allows the inclusion of these proteases as a potential candidate drug target for vivax malaria, while further investigations are still required to evaluate the activity, role and essentiality of metacaspases in P. vivax biology.
Topics: Plasmodium vivax; Brazil; Humans; Malaria, Vivax; Protozoan Proteins; Caspases; Gene Expression
PubMed: 38683374
DOI: 10.1007/s11033-024-09538-x -
Indian Journal of Nephrology 2024
PubMed: 38681005
DOI: 10.4103/ijn.ijn_206_23 -
Journal of Medicinal Chemistry May 2024-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high...
-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity. Various functional groups are appended to a pyrazole moiety in the inhibitor to target a pocket formed beneath the peptide binding cleft. The inhibitor core group polarity, lipophilicity, and size are also varied to probe the water structure near a channel. Selectivity index values range from 0.8 to 125.3. Cocrystal structures of two selective compounds, determined at 1.97 and 2.43 Å, show that extensions bind the targeted pocket but with different stabilities. A bulky naphthalene moiety introduced into the core binds next to instead of displacing protein-bound waters, causing a shift in the inhibitor position and expanding the binding site. Our structure-activity data provide a conceptual foundation for guiding future inhibitor optimizations.
Topics: Pyrazoles; Plasmodium vivax; Acyltransferases; Structure-Activity Relationship; Antimalarials; Enzyme Inhibitors; Crystallography, X-Ray; Humans; Models, Molecular; Binding Sites
PubMed: 38680035
DOI: 10.1021/acs.jmedchem.4c00168 -
Scientific Reports Apr 2024Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of...
Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of these proteins await elucidation, PvMSP3 has been suggested to be potential vaccine targets. To date, studies on natural immune responses to this protein family have been confined to two members, PvMSP3α and PvMSP3β. This study analyzed natural IgG antibody responses to PvMSP3γ recombinant proteins derived from two variants: one containing insert blocks (CT1230nF) and the other without insert domain (NR25nF). The former variant was also expressed as two subfragment proteins: one encompassing variable domain I and insert block A (CT1230N) and the other spanning from insert block B to conserved block III (CT1230C). Serum samples were obtained from 246 symptomatic vivax malaria patients in Tak (n = 50) and Ubon Ratchathani (n = 196) Provinces. In total, 176 (71.5%) patients could mount antibodies to at least one recombinant PvMSP3γ antigen. IgG antibodies directed against antigens CT1230nF, CT1230N, CT1230C and NR25nF occurred in 96.6%, 61.4%, 71.6% and 68.2% of samples, respectively, suggesting the widespread occurrence of B-cell epitopes across PvMSP3γ. The rates of seropositivity seemed to correlate with the number of previous malaria episodes. Isotype analysis of anti-PvMSP3γ antibodies has shown predominant cytophilic subclass responses, accounting for 75.4-81.7% for IgG1 and 63.6-77.5% for IgG3. Comparing with previous studies in the same cohort, the numbers of serum samples reactive to antigens derived from P. vivax merozoite surface protein 9 (PvMSP9) and thrombospondin-related anonymous protein (PvTRAP) were higher than those to PvMSP3γ, being 92.7% and 87.0% versus 71.5%, respectively. Three (1.22%) serum samples were nonresponsive to all these malarial proteins. Nevertheless, the relevance of naturally acquired antibodies to PvMSP3γ in host protection requires further studies.
Topics: Plasmodium vivax; Humans; Malaria, Vivax; Protozoan Proteins; Antigens, Protozoan; Antibodies, Protozoan; Immunoglobulin G; Male; Adult; Female; Middle Aged; Adolescent; Young Adult; Recombinant Proteins; Child
PubMed: 38671033
DOI: 10.1038/s41598-024-59153-w -
Insects Mar 2024The maintenance of a highly productive colony of anopheline mosquitoes requires standardized methods in order to obtain a sufficient number of homogeneous individuals...
The maintenance of a highly productive colony of anopheline mosquitoes requires standardized methods in order to obtain a sufficient number of homogeneous individuals for malaria research. In this context, nutritional status may affect survival, fecundity, and the capacity to support pathogen development. Here we assess the effects of carbohydrate sources on fecundity, survival, and susceptibility to infection in colonies of and mosquitoes. Newly emerged females from each species were fed either 10% sugar or 15% honey solutions until the end of each experiment. The type of carbohydrate meal did not impact any entomological parameters for , except for survival. For both species, honey meal significantly increased median survival post-emergence by three to four days, probably due to its nutritional value. For fed with honey, a higher mean frequency in stage 5 was observed at 48 h post-blood-meal, which could indicate a delay in the digestion process. However, no effects on fecundity parameters were observed. Regarding susceptibility, fed with sugar exhibited a low intensity of sporozoites, although any negative effects of sucrose on sporozoites invasions in the salivary glands are unknown. Based on the increase in mosquito survival, a carbohydrate source composed of 15% honey solution could be better for maintaining and in the lab-rearing context.
PubMed: 38667370
DOI: 10.3390/insects15040240 -
Malaria Journal Apr 2024Pregnancy Associated Malaria (PAM) include malaria in pregnancy (MiP), placental malaria (PM), and congenital malaria (CM). The evidence available in Colombia on PAM...
BACKGROUND
Pregnancy Associated Malaria (PAM) include malaria in pregnancy (MiP), placental malaria (PM), and congenital malaria (CM). The evidence available in Colombia on PAM focuses on one of the presentations (MiP, PM or CM), and no study longitudinally analyses the infection from the pregnant woman, passing through the placenta, until culminating in the newborn. This study determined the frequency of MiP, PM, and CM caused by Plasmodium vivax, Plasmodium falciparum, or mixed infections, according to Thick Blood Smear (TBS) and quantitative Polymerase Chain Reaction (qPCR). Identifying associated factors of PAM and clinical-epidemiological outcomes in northwestern Colombia.
METHODS
Prospective study of 431 pregnant women, their placenta, and newborns registered in the data bank of the research Group "Salud y Comunidad César Uribe Piedrahíta" which collected information between 2014 and 2020 in endemic municipalities of the departments of Córdoba and Antioquia. The frequency of infection was determined with 95% confidence intervals. Comparisons were made with the Chi-square test, Student t-test, prevalence ratios, and control for confounding variables by log-binomial regression.
RESULTS
The frequency of MiP was 22.3% (4.6% using TBS), PM 24.8% (1.4% using TBS), and CM 11.8% (0% using TBS). Using TBS predominated P. vivax. Using qPCR the proportions of P. vivax and P. falciparum were similar for MiP and PM, but P. falciparum predominated in CM. The frequency was higher in nulliparous, and women with previous malaria. The main clinical effects of PAM were anaemia, low birth weight, and abnormal APGAR score.
CONCLUSIONS
The magnitude of infections was not detected with TBS because most cases were submicroscopic (TBS-negative, qPCR-positive). This confirmed the importance of improving the molecular detection of cases. PAM continue being underestimated in the country due to that in Colombia the control programme is based on TBS, despite its outcomes on maternal, and congenital health.
Topics: Humans; Female; Pregnancy; Colombia; Prospective Studies; Adult; Malaria, Falciparum; Malaria, Vivax; Young Adult; Infant, Newborn; Pregnancy Complications, Parasitic; Adolescent; Plasmodium falciparum; Prevalence; Plasmodium vivax; Placenta; Placenta Diseases
PubMed: 38664687
DOI: 10.1186/s12936-024-04948-5 -
Emerging Infectious Diseases Jun 2024During May-July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the...
During May-July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.
Topics: Humans; Malaria, Vivax; Florida; Plasmodium vivax; Phylogeny; Male; Whole Genome Sequencing; Female; Adult; Middle Aged
PubMed: 38662728
DOI: 10.3201/eid3006.240336 -
BioRxiv : the Preprint Server For... Apr 202448/45, a gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we...
BACKGROUND
48/45, a gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we explored the cross-reactivity and TB activity of a recombinant 48/45 protein (r48/45) with sera from -exposed African donors.
METHODS
r48/45 was produced in Chinese hamster ovary cell lines and tested by ELISA for its cross-reactivity with sera from Burkina Faso, Tanzania, Mali, and Nigeria - In addition, BALB/c mice were immunized with the r48/45 protein formulated in Montanide ISA-51 and inoculated with a crude extract of NF-54 gametocytes to evaluate the parasite-boosting effect on r48/45 antibody titers. Specific anti-48/45 IgG purified from African sera was used to evaluate the TB activity on using standard mosquito membrane feeding assays (SMFA).
RESULTS
r48/45 protein showed cross-reactivity with sera of individuals from all four African countries, in proportions ranging from 94% (Tanzania) to 40% (Nigeria). Also, the level of cross-reactive antibodies varied significantly between countries (p<0.0001), with a higher antibody level in Mali and the lowest in Nigeria. In addition, antibody levels were higher in adults (≥ 17 years) than young children (≤ 5 years) in both Mali and Tanzania, with a higher proportion of responders in adults (90%) than in children (61%) (p<0.0001) in Mali, where male (75%) and female (80%) displayed similar antibody responses. Furthermore, immunization of mice with gametocytes boosted anti-48/45 antibody responses, recognizing gametocytes in indirect immunofluorescence antibody test. Notably, r48/45 affinity-purified African IgG exhibited a TB activity of 61% against in SMFA.
CONCLUSION
African sera (exposed only to cross-recognized the r48/45 protein. This, together with the functional activity of IgG, warrants further studies for the potential development of a and cross-protective TB vaccine.
PubMed: 38659832
DOI: 10.1101/2024.04.10.588966 -
Revista Do Instituto de Medicina... 2024Quilombo remnant communities are areas officially recognized by the Brazilian government as historical communities founded by formerly enslaved individuals. These...
Quilombo remnant communities are areas officially recognized by the Brazilian government as historical communities founded by formerly enslaved individuals. These communities are mostly located in the endemic areas of malaria in the Brazilian Amazon. We retrospectively described the prevalence of malaria among individuals living in 32 recognized quilombo remnant communities in the Baiao and Oriximina municipalities located in the Para State. The number of malaria cases and the Annual Parasitic Incidence (API) recorded by the Brazilian malaria surveillance system (SIVEP-Malaria) from January 2005 to December 2020 were analyzed. We found that all communities registered at least one case over the 16-year period, the most frequent parasitic species being Plasmodium vivax (76.1%). During this period, 0.44% (4,470/1,008,714) of the malaria cases registered in Para State were reported in these quilombo remnant communities, with frequencies of 10.9% (856/7,859) in Baiao municipality and 39.1% (3,614/9,238) in Oriximina municipality, showing that individuals living in these rural communities are exposed to malaria. These data indicate that effective surveillance requires improved measures to identify malaria transmission among vulnerable populations living in quilombo remnant communities in the Brazilian Amazon.
Topics: Humans; Brazil; Cross-Sectional Studies; Retrospective Studies; Prevalence; Vulnerable Populations; Malaria, Vivax; Incidence; Female; Male; Adult; Rural Population; Adolescent; Malaria; Young Adult; Child; Middle Aged; Malaria, Falciparum; Child, Preschool
PubMed: 38656041
DOI: 10.1590/S1678-9946202466025 -
Journal of Medicinal Chemistry May 2024Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA...
Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by and , , , and . Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme. X-ray crystal structures show that, on binding, these prolinol-containing inhibitors stimulated the movement of active site loops in the enzyme. Against in cell culture, a prodrug exhibited an EC of 10 μM. Thus, these compounds are excellent candidates for further development as drug leads against infectious diseases as well as being potential anticancer agents.
Topics: Drug Design; Pentosyltransferases; Enzyme Inhibitors; Structure-Activity Relationship; Crystallography, X-Ray; Humans; Models, Molecular; Trypanosoma brucei brucei; Molecular Structure; Catalytic Domain
PubMed: 38651522
DOI: 10.1021/acs.jmedchem.4c00021