Plasmodium Research Articles

Epidemiological profile of malaria in a rural community in the Amazon, Mato Grosso State, Brazil, 2011

BackgroundMore than 95% of malaria transmission in Brazil occurs in the Legal Amazon Region, which in 2010 recorded around 333,429 cases reported in the Epidemiological Surveillance Information System-Malaria (Sivep_malaria), presenting an annual parasitic incidence (IPA) of 13.1 cases/1000 inhabitants.MethodsThis was a descriptive study that measured the community prevalence of Plasmodium infection and its relationship with land use in Três Fronteiras District, Colniza Municipality, Mato Grosso State. Data were collected during household visits in July 2011, with blood collection from finger pricks for the preparation of thick smear slides, and completion of a standardized case notification form. A georeferenced database was analysed, with land use evaluated as categorical variables. A kernel density map was built to show the density of cases and their location.ResultsOf the 621 respondents, 68(11%) had Plasmodium infection: 39 (57.4%) with Plasmodium vivax, 27(39.7%) with Plasmodium falciparum and two (2.9%) with mixed infections. Among infected individuals, 49 (72.1%) were men. Cases of malaria were distributed over the district, with greater occurrence of cases per household in open areas close to the mining company and artisanal mining sites. The was a greater density of cases located in the gold mining region.ConclusionTransmission of malaria in Três Fronteiras District has a heterogeneous distribution. Individuals residing in mining and timber extraction sites have increased occurrence of Plasmodium infection.

Copy Number Variations of Plasmodium vivax DBP1, EBP/DBP2, and RBP2b in Ethiopians Who Are Duffy Positive and Duffy Negative.

Recent evidence challenges the belief that individuals who are Duffy-negative are resistant to Plasmodium vivax due to lacking the Duffy antigen receptor for chemokines. Erythrocyte-binding protein (EBP/DBP2) has shown moderate binding to Duffy-negative erythrocytes in vitro. Reticulocyte-binding protein 2b (RBP2b) interactions with transferrin receptor 1 suggest involvement in Duffy-negative infections. Gene copy number variations in PvDBP1, PvEBP/DBP2, and PvRBP2b were investigated in Duffy-positive and Duffy-negative P vivax infections from Ethiopia. Among Duffy-positive samples, 34% displayed PvDBP1 duplications (Cambodian type). In Duffy-negative infections, 30% showed duplications, mostly Cambodian type. For PvEBP/DBP2 and PvRBP2b, Duffy-positive samples exhibited higher duplication rates (1-8 copies for PvEBP/DBP2, 46%; 1-5 copies for PvRBP2b, 43%) as compared with Duffy-negative samples (20.8% and 26%, respectively). The range of copy number variations was lower in Duffy-negative infections. Demographic and clinical factors associated with gene multiplications in both Duffy types were explored, enhancing understanding of P vivax evolution in Africans who are Duffy negative.

Does host migration affect host-parasite interaction? Migrant birds harbor exclusive parasites but have similar roles in parasite-host networks.

Parasites comprise a substantial portion of global biodiversity and play critical roles in shaping ecosystems by modulating trophic networks and affecting their hosts' abundance and distribution. The dynamics of host migration introduce new complexity to these relationships. From the host perspective, migratory behavior can either act as a defense mechanism or augment exposure to a broader spectrum of pathogens. Conversely, for parasites, host migration represents a mechanism for their dispersion and an opportunity to infect new host species. This study investigates the complex interplay between migration and parasite-host interactions, focusing on the interaction between hosts and avian malaria and malaria-like parasites in the Brazilian Atlantic Rain Forest. We captured 1466 birds representing 70 different species, uncovering 322 infections with Plasmodium/Haemoproteus parasites. We observed variations in migration timing and fluctuations in host abundance across months. By comparing the observed patterns of interaction of migratory and non-migratory birds to patterns of interaction expected at random, we show that migration affects the roles hosts take in the parasite-host network. Interestingly, despite the fact migratory species hosted more exclusive and distinct parasites, migrants did not occupy central network positions, which are mostly occupied by resident birds. Overall, we highlight the role of resident birds as a key species within parasite-host communities and the high specialization among avian haemosporidians and their hosts.

A transfer learning approach to identify Plasmodium in microscopic images.

Plasmodium parasites cause Malaria disease, which remains a significant threat to global health, affecting 200 million people and causing 400,000 deaths yearly. Plasmodium falciparum and Plasmodium vivax remain the two main malaria species affecting humans. Identifying the malaria disease in blood smears requires years of expertise, even for highly trained specialists. Literature studies have been coping with the automatic identification and classification of malaria. However, several points must be addressed and investigated so these automatic methods can be used clinically in a Computer-aided Diagnosis (CAD) scenario. In this work, we assess the transfer learning approach by using well-known pre-trained deep learning architectures. We considered a database with 6222 Region of Interest (ROI), of which 6002 are from the Broad Bioimage Benchmark Collection (BBBC), and 220 were acquired locally by us at Fundação Oswaldo Cruz (FIOCRUZ) in Porto Velho Velho, Rondônia-Brazil, which is part of the legal Amazon. We exhaustively cross-validated the dataset using 100 distinct partitions with 80% train and 20% test for each considering circular ROIs (rough segmentation). Our experimental results show that DenseNet201 has a potential to identify Plasmodium parasites in ROIs (infected or uninfected) of microscopic images, achieving 99.41% AUC with a fast processing time. We further validated our results, showing that DenseNet201 was significantly better (99% confidence interval) than the other networks considered in the experiment. Our results support claiming that transfer learning with texture features potentially differentiates subjects with malaria, spotting those with Plasmodium even in Leukocytes images, which is a challenge. In Future work, we intend scale our approach by adding more data and developing a friendly user interface for CAD use. We aim at aiding the worldwide population and our local natives living nearby the legal Amazon's rivers.

Non-random distribution of Plasmodium Species infections and associated clinical features in children in the lake Victoria region, Kenya, 2012–2018

BackgroundWhile Plasmodium falciparum (Pf) stands out as the most lethal malaria parasite species in humans, the impact of other species should not be dismissed. Moreover, there is a notable lack of understanding of mixed-species infections and their clinical implications.MethodsWe conducted eight school-based cross-sectional malariometric surveys in the Lake Victoria region of western Kenya between January–February 2012 and September–October 2018. In each survey, a minimum of 100 children aged 3 to 15 years were randomly chosen from a school in Ungoye village on the mainland and as well as from each school selected in every catchment area on Mfangano island. Plasmodium infection was determined by microscopy and nested polymerase chain reaction (PCR). The multiple-kind lottery (MKL) model calculated the expected distribution of Plasmodium infections in the population and compared it to observed values using a chi-squared test (χ2).ResultsThe Plasmodium prevalence was 25.9% (2521/9724) by microscopy and 51.1% (4969/9724) by PCR. Among all infections detected by PCR, Pf, P. malariae (Pm), and P. ovale (Po) mono-infections were 58.6%, 3.1%, and 1.8%, respectively. Pf/Pm, Pf/Po, Pm/Po, and Pf/Pm/Po co-infections were 23.5%, 4.3%, 0.1%, and 8.6%, respectively. MKL modelling revealed non-random distributions, with frequencies of Pf/Pm and Pf/Pm/Po co-infections being significantly higher than expected (χ2 = 3385.60, p < 0.001). Pf co-infections with Pm and Po were associated with a decreased risk of fever (aOR 0.64, 95% CI 0.46–0.83; p = 0.01) and increased risks of splenomegaly (aOR 12.79, 95% CI 9.69–16.9; p < 0.001) and anaemia (aOR 2.57, 95% CI 2.09–3.15; p < 0.001), compared to single-species infections.ConclusionThis study sheds light on the potential interaction between Pf and Pm and/or Po. Given the clinical significance of mixed-species infections, improved diagnostics, and case management of Pm and Po are urgently needed.

Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites

Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.

Spatiotemporal patterns and association with climate for malaria elimination in Lao PDR: a hierarchical modelling analysis with two-step Bayesian model selection

BackgroundThe government of Lao PDR has increased efforts to control malaria transmission in order to reach its national elimination goal by 2030. Weather can influence malaria transmission dynamics and should be considered when assessing the impact of elimination interventions but this relationship has not been well characterized in Lao PDR. This study examined the space–time association between climate variables and Plasmodium falciparum and Plasmodium vivax malaria incidence from 2010 to 2022.MethodsSpatiotemporal Bayesian modelling was used to investigate the monthly relationship, and model selection criteria were used to evaluate the performance of the models and weather variable specifications. As the malaria control and elimination situation was spatially and temporally dynamic during the study period, the association was examined annually at the provincial level.ResultsMalaria incidence decreased from 2010 to 2022 and was concentrated in the southern regions for both P. falciparum and P. vivax. Rainfall and maximum humidity were identified as most strongly associated with malaria during the study period. Rainfall was associated with P. falciparum incidence in the north and central regions during 2010–2011, and with P. vivax incidence in the north and central regions during 2012–2015. Maximum humidity was persistently associated with P. falciparum and P. vivax incidence in the south.ConclusionsMalaria remains prevalent in Lao PDR, particularly in the south, and the relationship with weather varies between regions but was strongest for rainfall and maximum humidity for both species. During peak periods with suitable weather conditions, vector control activities and raising public health awareness on the proper usage of intervention measures, such as indoor residual spraying and personal protection, should be prioritized.

The clinical, hematological, and biochemical profiles of patients with complications due to Plasmodium vivax malaria: A case series

Malaria, a protozoal infection caused by the six species of the genus Plasmodium, is one of the most important diseases known to humankind, with most infections caused by either of the two species – Plasmodium vivax and Plasmodium falciparum. Previously, it was held that falciparum malaria was responsible for causing severe, life-threatening disease, with vivax malaria causing mild or uncomplicated infections. In this case series, the clinical, hematological, and biochemical profiles of eight patients with features of complications due to P. vivax malaria, along with their clinical course, response to treatment, and clinical outcomes have been described. Among these, the most common clinical features were fever, headache, and myalgias. Five patients had altered mental status, two were prostrated, two were hypotensive, and one had recurrent generalized seizures. Three patients had pancytopenia, two had both anemia and thrombocytopenia, and one had evidence of disseminated intravascular coagulation. Six patients had clinical jaundice, four had elevated transaminases, and four had acute kidney injury. All cases showed excellent response to anti-malarial therapy. Hence, this case series revealed that P. vivax is capable of causing severe, life-threatening organ dysfunction akin to those seen in P. falciparum malaria and that early diagnosis and treatment initiation are associated with positive patient end outcomes.

Primaquine-5,6-Orthoquinone Is Directly Hemolytic to Older G6PD Deficient RBCs in a Humanized Mouse Model.

Primaquine and Tafenoquine are the only approved drugs that can achieve a radical cure for Plasmodium vivax malaria but are contraindicated in patients who are deficient in glucose 6-phosphate dehydrogenase (G6PDd) due to risk of severe hemolysis from reactive oxygen species generated by redox cycling of drug metabolites. 5-hydroxyprimaquine and its quinoneimine cause robust redox cycling in red blood cells (RBCs) but are so labile as to not be detected in blood or urine. Rather, the quinoneimine is rapidly converted into primaquine-5,6-orthoquinone (5,6-POQ) that is then excreted in the urine. The extent to which 5,6-POQ contributes to hemolysis remains unclear, although some have suggested that it is a minor toxin that should be used predominantly as a surrogate to infer levels of 5-hydroxyprimaquine. In this report, we describe a novel humanized mouse model of the G6PD Mediterranean variant (hG6PDMed-) that recapitulates the human biology of RBC age-dependent enzyme decay, as well as an isogenic matched control mouse with human nondeficient G6PD hG6PDND In vitro challenge of RBCs with 5,6-POQ causes increased generation of superoxide and methemoglobin. Infusion of treated RBCs shows that 5,6-POQ selectively causes in vivo clearance of older hG6PDMed- RBCs. These findings support the hypothesis that 5,6-POQ directly induces hemolysis and challenges the notion that 5,6-POQ is an inactive metabolic waste product. Indeed, given the extreme lability of 5-hydroxyprimaquine and the relative stability of 5,6-POQ, these data raise the possibility that 5,6-POQ is a major hemolytic primaquine metabolite in vivo. SIGNIFICANCE STATEMENT: These findings demonstrate that 5,6-POQ, which has been considered an inert waste product of primaquine metabolism, directly induces ROS that cause clearance of older G6PDd RBCs. As 5,6-POQ is relatively stable compared with other active primaquine metabolites, these data support the hypothesis that 5,6-POQ is a major toxin in primaquine induced hemolysis. The findings herein also establish a new model of G6PDd and provide the first direct evidence, to our knowledge, that young G6PDd RBCs are resistant to primaquine-induced hemolysis.

MOIRE: A software package for the estimation of allele frequencies and effective multiplicity of infection from polyallelic data.

Malaria parasite genetic data can provide insight into parasite phenotypes, evolution, and transmission. However, estimating key parameters such as allele frequencies, multiplicity of infection (MOI), and within-host relatedness from genetic data has been challenging, particularly in the presence of multiple related coinfecting strains. Existing methods often rely on single nucleotide polymorphism (SNP) data and do not account for within-host relatedness. In this study, we introduce a Bayesian approach called MOIRE (Multiplicity Of Infection and allele frequency REcovery), designed to estimate allele frequencies, MOI, and within-host relatedness from genetic data subject to experimental error. Importantly, MOIRE is flexible in accommodating both polyallelic and SNP data, making it adaptable to diverse genotyping panels. We also introduce a novel metric, the effective MOI (eMOI), which integrates MOI and within-host relatedness, providing a robust and interpretable measure of genetic diversity. Using extensive simulations and real-world data from a malaria study in Namibia, we demonstrate the superior performance of MOIRE over naive estimation methods, accurately estimating MOI up to 7 with moderate sized panels of diverse loci (e.g. microhaplotypes). MOIRE also revealed substantial heterogeneity in population mean MOI and mean relatedness across health districts in Namibia, suggesting detectable differences in transmission dynamics. Notably, eMOI emerges as a portable metric of within-host diversity, facilitating meaningful comparisons across settings, even when allele frequencies or genotyping panels are different. MOIRE represents an important addition to the analysis toolkit for malaria population dynamics. Compared to existing software, MOIRE enhances the accuracy of parameter estimation and enables more comprehensive insights into within-host diversity and population structure. Additionally, MOIRE's adaptability to diverse data sources and potential for future improvements make it a valuable asset for research on malaria and other organisms, such as other eukaryotic pathogens. MOIRE is available as an R package at https://eppicenter.github.io/moire/.

Performance of rapid diagnostic test, light microscopy, and polymerase chain reaction in pregnant women with asymptomatic malaria in Nigeria

ObjectivesRapid diagnostic tests (RDTs) offer an attractive tool for diagnosing malaria in pregnancy. This study assessed the effectiveness of a Plasmodium falciparum–specific RDT compared with microscopy and polymerase chain reaction (PCR) in diagnosing asymptomatic malaria in pregnant women in southwest Nigeria. MethodsThe study included 406 asymptomatic pregnant women seeking antenatal care. Blood samples were collected and tested using RDT (SD Bioline, Standard Diagnostics Inc. Korea) and light microscopy and confirmed using nested PCR. ResultsThe study revealed that the malaria parasite positivity rate was 8.9% by RDT, 21% by microscopy, and 32% by nested PCR. RDT had a sensitivity of 51.4% and specificity of 69.5%, whereas microscopy had a sensitivity of 65.3% and specificity of 98.2%. The combined testing of microscopy and RDT had a sensitivity and specificity of 100%. The study also showed a high prevalence of mild anemia among participants. ConclusionsDespite the RDT's low sensitivity, its high negative predictive value suggests it could be useful in combination with microscopy in ruling out asymptomatic malaria in pregnancy. Further study will help identify more suitable RDTs for routine malaria diagnosis in Nigeria and strengthen malaria prevention programs in pregnant women.

Structure-based design of a Plasmodium vivax Duffy-binding protein immunogen focuses the antibody response to functional epitopes.

The Duffy-binding protein (DBP) is a promising antigen for a malaria vaccine that would protect against clinical symptoms caused by Plasmodium vivax infection. Region II of DBP (DBP-II) contains the receptor-binding domain that engages host red blood cells, but DBP-II vaccines elicit many non-neutralizing antibodies that bind distal to the receptor-binding surface. Here, we engineered a truncated DBP-II immunogen that focuses the immune response to the receptor-binding surface. This immunogen contains the receptor-binding subdomain S1S2 and lacks the immunodominant subdomain S3. Structure-based computational design of S1S2 identified combinatorial amino acid changes that stabilized the isolated S1S2 without perturbing neutralizing epitopes. This immunogen elicited DBP-II-specific antibodies in immunized mice that were significantly enriched for blocking activity compared to the native DBP-II antigen. This generalizable design process successfully stabilized an integral core fragment of a protein and focused the immune response to desired epitopes to create a promising new antigen for malaria vaccine development.

Immunogenic and diagnostic potential of recombinant apical membrane antigen-1 from Plasmodium malariae

The apical membrane antigen-1 (AMA-1) is a crucial target for malaria management and prevention strategies. While the immunogenicity of AMA-1 has been extensively studied for Plasmodium falciparum and Plasmodium vivax, there is a notable scarcity of information for Plasmodium malariae. In this study, recombinant PmAMA-1 was expressed in Escherichia coli, and its integrity was confirmed via western blotting and indirect immunofluorescence assays. Immunization of BALB/c mice with rPmAMA-1 emulsified in Freund's adjuvant resulted in significantly elevated specific IgG antibodies, predominantly IgG1. The immune response exhibited Th1, Th2, and Th17 phenotypes, with a notable Th1 bias. Antisera from immunized mice effectively recognized native PmAMA-1 on P. malariae. These results suggest that PmAMA-1 is a promising target for both vaccine development and diagnostic applications for P. malariae infections, offering dual preventive and diagnostic benefits in malaria control.

Population genetic analysis of Plasmodium vivax vir genes in Pakistan.

Plasmodium vivax variant interspersed repeats (vir) refer to the key protein used for escaping the host immune system. Knowledge in the genetic variation of vir genes can be used for the development of vaccines or diagnostic methods. Therefore, we evaluated the genetic diversity of the vir genes of P. vivax populations of several Asian countries, including Pakistan, which is a malaria-endemic country experiencing a significant rise in malaria cases in recent years. We analyzed the genetic diversity and population structure of 4 vir genes (vir 4, vir 12, vir 21, and vir 27) in the Pakistan P. vivax population and compared these features to those of the corresponding vir genes in other Asian countries. In Pakistan, vir 4 (S=198, H=9, Hd=0.889, Tajima's D value=1.12321) was the most genetically heterogenous, while the features of vir 21 (S=8, H=7, Hd=0.664, Tajima's D value =-0.63763) and vir 27 (S =25, H =11, Hd =0.682, Tajima's D value=-2.10836) were relatively conserved. Additionally, vir 4 was the most genetically diverse among Asian P. vivax populations, although within population diversity was low. Meanwhile, vir 21 and vir 27 among all Asian populations were closely related genetically. Our findings on the genetic diversity of vir genes and its relationships between populations in diverse geographical locations contribute toward a better understanding of the genetic characteristics of vir. The high level of genetic diversity of vir 4 suggests that this gene can be a useful genetic marker for understanding the P. vivax population structure. Longitudinal genetic diversity studies of vir genes in P. vivax isolates obtained from more diverse geographical areas are needed to better understand the function of vir genes and their use for the development of malaria control measures, such as vaccines.

Mosquito prevalence, resting habitat preference, and Plasmodium infection status of anophelines in coastal Karnataka during the declining phase of malaria—an exploratory study

Malaria has a historical presence in the Dakshina Kannada (D.K.) and Udupi districts of Karnataka, India. To understand the potential involvement of anopheline fauna in malaria transmission, we conducted an exploratory entomological survey. The study is crucial given the decreasing malaria incidence in these districts in recent years. From September 2022 to August 2023, we collected indoor resting mosquitoes using a manual aspirator at 27 randomly chosen sites within three distinct resting habitats (human dwellings, cattle sheds, and construction sites) in the urban areas of Udupi and Dakshina Kannada districts. Mosquitoes were morphologically identified, and anopheline specimens were tested for the presence of malarial parasite by polymerase chain reaction (PCR) analysis. We collected a total of 1810 mosquitoes, comprising 21 species distributed across five genera. Culex emerged as the predominant genus, constituting 84.4% of the collected specimens, while Anopheles accounted for 5.4%. Among the observed species, Culex quinquefasciatus was predominant, comprising 77.9% of the mosquito specimens collected in this study. Two malaria vectors, An. stephensi and An. subpictus complex, constituted 16.3% and 1.0% of the total anophelines collected, respectively. None of the 96 female anophelines was tested positive for Plasmodium infection. Our findings suggest that Anopheles mosquitoes prefer resting in cattle sheds over human dwellings. While our study identified two malaria vectors, they were present at low densities. To gain a more comprehensive understanding of the dynamics of these vector mosquitoes, it is essential to conduct long-term surveillance to monitor their prevalence and role in malaria transmission.

Antiplasmodial action of 4-nitrobenzenesulfonamide chalcones: Design, synthesis, characterisation, in vitro and in silico evaluation against blood stages of Plasmodium falciparum 3D7.

Malaria is an intracellular protozoan parasitic disease caused by Plasmodium species with significant morbidity and mortality in endemic regions. The complex lifecycle of the parasite and the emergence of drug-resistant Plasmodium falciparum have hampered the efficacy of current anti-malarial agents. To circumvent this situation, the present study attempts to demonstrate the blood-stage anti-plasmodial action of 26 hybrid compounds containing the three privileged bioactive scaffolds (sulfonamide, chalcone, and nitro group) with synergistic and multitarget action. These three parent scaffolds exhibit divergent activities, such as antibacterial, anti-malarial, anti-fungal, anti-inflammatory, and anticancer. All the synthesised compounds were characterised using various spectroscopic techniques. The in vitro blood-stage inhibitory activity of 26 hybrid compounds was evaluated against mixed-stage culture (asynchronize) of human malarial parasite P. falciparum, Pf 3D7 at different concentrations ranging from 25.0 µg/mL to 0.78 µg/mL using SYBR 1 green assay, with IC50 values determined after 48 h of treatment based on the drug-response curves. Two potent compounds (11 and 10), with 2-Br and 2,6-diCl substitutions, showed pronounced activity with IC50 values of 5.4 µg/mL and 5.6 µg/mL, whereas others displayed varied activity with IC50 values ranging from 7.0 µg/mL to 22.0 µg/mL. Both 11 and 10 showed greater susceptibility towards mature-stage trophozoites than ring-stage parasites. The hemolytic and in vitro cytotoxicity assays revealed that compounds 11 and 10 did not cause any toxic effects on host red blood cells (uninfected), human-derived Mo7e cells, and murine-derived BA/F3 cells. The in vitro observations are consistent with the in silico studies using P. falciparum-dihydrofolate reductase, where 11 and 10 showed a binding affinity of -10.4 Kcal/mol. This is the first report of the hybrid scaffold, 4-nitrobenzenesulfonamide chalcones, demonstrating its potential as an anti-plasmodial agent.

Dual nature of type I interferon responses and feedback regulations by SOCS1 dictate malaria mortality

IntroductionType I interferon (IFN-I, IFN-α/β), precisely controlled by multiple regulators, including suppressor of cytokine signaling 1 (SOCS1), is critical for host defense against pathogens. However, the impact of IFN-α/β on malaria parasite infections, beneficial or detrimental, remains controversial. ObjectivesThe contradictory results are suspected to arise from differences in parasite species and host genetic backgrounds. To date, no prior study has employed a comparative approach utilizing two parasite models to investigate the underlying mechanisms of IFN-I response. Moreover, whether and how SOCS1 involves in the distinct IFN-α/β dynamics is still unclear. MethodsHere we perform single-cell RNA sequencing analyses (scRNA-seq) to dissect the dynamics of IFN-α/β responses against P. yoelii 17XL (17XL) and P. berghei ANKA (PbANKA) infections; conduct flow cytometry analysis and functional depletion to identify key cellular players induced by IFN-I; and establish mathematical models to explore the mechanisms underlying the differential IFN-I dynamics regulated by SOCS1. Results17XL stimulates an early protective but insufficient toll-like receptor 7 (TLR7)-interferon regulatory factor 7 (IRF7)-dependent IFN-α/β response, resulting in CD11ahiCD49dhiCD4+ T cell activation to enhance anti-malarial immunity. On the contrary, a late IFN-α/β induction through toll-like receptor 9 (TLR9)-IRF7/ stimulator of interferon genes (STING)- interferon regulatory factor 3 (IRF3) dependent pathways expands programmed cell death protein 1 (PD-1)+CD8+ T cells and impairs host immunity during PbANKA infection. Furthermore, functional assay and mathematical modeling show that SOCS1 significantly suppresses IFN-α/β production via negative feedback and incoherent feed-forward loops (I1-FFL). Additionally, differential activation patterns of various transcriptional factors (TFs) synergistically regulate the distinct IFN-I responses. ConclusionThis study reveals the dual functions of IFN-I in anti-malarial immunity: Early IFN-α/β enhances immune responses against Plasmodium infection by promoting CD11ahiCD49dhiCD4+ T cell, while late IFN-α/β suppresses these response by expanding PD-1+CD8+ T cells. Moreover, both the SOCS1-related network motifs and TFs activation patterns contribute to determine distinct dynamics of IFN-I responses. Hence, our findings suggest therapies targeting SOCS1- or TFs-regulated IFN-I dynamics could be an efficacious approach for preventing malaria and enhancing vaccine efficacy.

Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC50 550 nM; 3 96 h IC50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements.

Ronald Ross: Pioneer of Malaria Research and Nobel Laureate.

Sir Ronald Ross, a British medical doctor and researcher, is renowned for his pioneering work in malaria research. His discovery of the malaria parasite's lifecycle within mosquitoes revolutionized the understanding and control of malaria, transitioning the field from the miasma theory to vector-based strategies. This literature review aims to explore the comprehensive contributions of Ronald Ross to malaria researchand their enduring impact on public health.

Insights into Peptidyl-Prolyl cis-trans Isomerases from Clinically Important Protozoans: From Structure to Potential Biotechnological Applications.

Peptidyl-prolyl cis/trans isomerases (PPIases) are present in a wide variety of microorganisms, including protozoan parasites such as Trypanosoma cruzi, Trypanosoma brucei, Trichomonas vaginalis, Leishmania major, Leishmania donovani, Plasmodium falciparum, Plasmodium vivax, Entamoeba histolytica, Giardia intestinalis, Cryptosporidium parvum, and Cryptosporidium hominis, all of which cause important neglected diseases. PPIases are classified as cyclophilins, FKBPs, or parvulins and play crucial roles in catalyzing the cis-trans isomerization of the peptide bond preceding a proline residue. This activity assists in correct protein folding. However, experimentally, the biological structure-function characterization of PPIases from these protozoan parasites has been poorly addressed. The recombinant production of these enzymes is highly relevant for this ongoing research. Thus, this review explores the structural diversity, functions, recombinant production, activity, and inhibition of protozoan PPIases. We also highlight their potential as biotechnological tools for the in vitro refolding of other recombinant proteins from these parasites. These applications are invaluable for the development of diagnostic and therapeutic tools.