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Scientific Reports Jun 2024Malaria in eastern Indonesia remains high despite significant reduction and elimination in other parts of the country. A rapid entomological assessment was conducted in...
Malaria in eastern Indonesia remains high despite significant reduction and elimination in other parts of the country. A rapid entomological assessment was conducted in eight high malaria endemic regencies of Papua Province, Indonesia, to expedite malaria elimination efforts in this region. This study aims to characterize specific, actionable endpoints toward understanding where and when malaria transmission is happening, where interventions may function best, and identify gaps in protection that result in continued transmission. The entomological assessment included identifying potential vectors through human landing catch (HLC), indoor morning and night resting collections, identification of larval sites through surveillance of water bodies, and vector incrimination toward understanding exposure to malaria transmission. Human landing catches (HLCs) and larval collections identified 10 Anopheles species, namely Anopheles koliensis, Anopheles punctulatus, Anopheles farauti, Anopheles hinesorum, Anopheles longirostris, Anopheles peditaeniatus, Anopheles tesselatus, Anopheles vagus, Anopheles subpictus and Anopheles kochi. The most common and abundant species found overall were An. koliensis and An. punctulatus, while An. farauti was found in large numbers in the coastal areas of Mimika and Sarmi Regencies. Vector incrimination on Anopheles collected from HLCs and night indoor resting demonstrated that An. koliensis and An. punctulatus carried Plasmodium in Keerom, Jayapura, and Sarmi Regencies. Analysis of HLCs for the most common species revealed that the An. koliensis and An. punctulatus, bite indoors and outdoors at equal rates, while An. farauti predominantly bite outdoors. Larval surveillance demonstrated that most water bodies in and surrounding residential areas contained Anopheles larvae. This study demonstrated indoor and outdoor exposure to mosquito bites and gaps in protection, enabling exposure to infectious bites in all regencies. This explains why current malaria control efforts focusing on indoor protection have failed to substantially reduce malaria incidence in the region. Optimization of insecticide-treated bed nets (ITNs), as well as installment of mosquito screens in houses, may further reduce indoor transmission. For outdoor transmission, the use of community-centric approaches to reduce or eliminate larval sources within and surrounding the village through the guidance of locally stationed entomologists, along with Social and Behavior Change mediated health education towards the local adoption of mosquito protection tools during outdoor activities, may reduce malaria transmission.
Topics: Animals; Anopheles; Malaria; Humans; Mosquito Vectors; Indonesia; Larva; Endemic Diseases
PubMed: 38918533
DOI: 10.1038/s41598-024-64958-w -
Journal of Medicinal Chemistry Jun 2024Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of () phosphatidylinositol-4-kinase β (PI4K),...
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors of () phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at 8-position, which retained PI4K inhibitory activity but switched primary mode of action to the host hemoglobin degradation pathway through inhibition of hemozoin formation. These compounds showed minimal off-target inhibitory activity against the human phosphoinositide kinases and MINK1 and MAP4K kinases, which were associated with the teratogenicity and testicular toxicity observed in rats for the PI4K inhibitor clinical candidate MMV390048. A representative compound from the series retained activity against field isolates and lab-raised drug-resistant strains of . It was efficacious in the humanized NSG mouse malaria infection model at a single oral dose of 32 mg/kg. This compound was nonteratogenic in the zebrafish embryo model of teratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate for malaria.
PubMed: 38918002
DOI: 10.1021/acs.jmedchem.4c01154 -
The American Journal of Tropical... Jun 2024Haiti is endemic for lymphatic filariasis (LF) and malaria, two mosquito-transmitted parasitic diseases targeted for elimination. The World Health Organization...
Haiti is endemic for lymphatic filariasis (LF) and malaria, two mosquito-transmitted parasitic diseases targeted for elimination. The World Health Organization recommends a transmission assessment survey (TAS-1) to determine if LF prevalence is significantly beneath putative transmission thresholds (<2% antigen prevalence in Haiti, where Culex is the primary vector for Wuchereria bancrofti) to stop mass drug administration (MDA). Repeated TASs (TAS-2 and TAS-3) are recommended at 2-3-year intervals during post-treatment surveillance. From 2017 to 2022, The Carter Center assisted the Haitian Ministry of Public Health and Population in conducting 15 TASs in 11 evaluation units (EUs) encompassing 54 of the country's 146 districts. Children 6-7 years old were assessed for circulating filarial antigen (CFA) by Filariasis Test Strip: n = 5,239 in TAS-1; n = 11,866 in TAS-2; and n = 1,842 in TAS-3, of whom eight (0.15%), 20 (0.17%), and eight (0.43%) tested positive, respectively. The number of positive results in children was less than the threshold in each EU. When available, participants (n = 16,663) were also tested for malaria by rapid diagnostic test, with 31 (0.19%) children testing positive for Plasmodium falciparum. Integrated TASs provided an efficient means to collect epidemiological data for LF and malaria in Haiti. Results indicated thresholds for stopping and maintaining the halt of MDA for LF have been achieved in all EUs, with the halt of MDA for 571,358 people in four districts and the first TAS-3 surveys conducted in Haiti. Investigations are needed to assess the potential of ongoing LF transmission, especially in areas where CFA-positive samples were detected in TAS-3.
PubMed: 38917782
DOI: 10.4269/ajtmh.23-0765 -
ImmunoHorizons Jun 2024Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized...
Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.
Topics: Animals; Macrophages; Mice; Erythrocytes; Malaria; Plasmodium berghei; Circadian Rhythm; Mice, Inbred C57BL; Reactive Oxygen Species; Cytokines; Circadian Clocks; Cells, Cultured; Proteome
PubMed: 38916585
DOI: 10.4049/immunohorizons.2400021 -
Cureus May 2024Prompt diagnosis of malaria infection is critical for effective management, yet it can be challenging due to varying incubation periods and the need for...
Prompt diagnosis of malaria infection is critical for effective management, yet it can be challenging due to varying incubation periods and the need for physician-initiated laboratory workups. We present a case of a 40-year-old male with fever and dark-colored urine, initially evaluated for sepsis. Plasmodium vivax was incidentally identified on a peripheral smear review after obtaining a remote travel history from a malaria-endemic area. Consultation with the Centers for Disease Control confirmed the diagnosis, emphasizing the importance of thorough travel history assessment and timely laboratory investigation in suspected cases of malaria. This case underscores the significance of early diagnosis in managing this potentially life-threatening infection.
PubMed: 38916004
DOI: 10.7759/cureus.61077 -
Scientific Reports Jun 2024Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic...
LLIN Evaluation in Uganda Project (LLINEUP)-effects of a vector control trial on Plasmodium infection prevalence and genotypic markers of insecticide resistance in Anopheles vectors from 48 districts of Uganda.
Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic resistance. In 2017-2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus PBO (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, we conducted cross-sectional household entomological surveys at baseline and then every 6 months for two years, which we use here to investigate longitudinal changes in mosquito infection rate and genetic markers of resistance. Overall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected (PCR-positive) with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s., but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutation Vgsc-995S declined over time as Vgsc-995F, the alternative resistance mutation at this codon, increased. Vgsc-995F appears to be spreading into Uganda. Distribution of LLINs in Uganda was previously found to be associated with reductions in parasite prevalence and vector density, but here we show that the proportion of infective mosquitoes remained stable across both PBO and non-PBO LLINs, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies.Trial registration: This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395 .
Topics: Animals; Anopheles; Insecticide Resistance; Uganda; Mosquito Vectors; Insecticide-Treated Bednets; Mosquito Control; Humans; Pyrethrins; Insecticides; Malaria; Female; Plasmodium falciparum; Prevalence; Genetic Markers; Cross-Sectional Studies; Malaria, Falciparum; Piperonyl Butoxide; Genotype
PubMed: 38914669
DOI: 10.1038/s41598-024-65050-z -
MBio Jun 2024Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been...
Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the () and increased copies of (). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) allele and a single copy of , while KH004 has a chloroquine-resistant (Dd2-like) allele with an additional G367C substitution and multiple copies of . We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at and . We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC. We find that inheritance of the KH004 allele is required for reduced PPQ sensitivity, whereas copy number variation in further decreases susceptibility but does not confer resistance in the absence of additional mutations in . A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions , , and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 was inherited among the progeny clones, allowing us to directly test the role of the copy number on resistance-related phenotypes in the context of a unique allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.
PubMed: 38912775
DOI: 10.1128/mbio.00805-24 -
Biology Open Jun 2024Myxomycetes are multinucleate unicellular organisms. They form a plasmodium that moves by protoplasmic flow and prey on microorganisms. When encountering intraspecifics,...
Myxomycetes are multinucleate unicellular organisms. They form a plasmodium that moves by protoplasmic flow and prey on microorganisms. When encountering intraspecifics, the plasmodium has the capacity for 'fusion,' actively approaching and fusing its cells, or 'avoidance,' altering its direction to avoid the other individual. This is an allorecognition ability. However, it remains unclear whether the range of allorecognition extends to other species, and its ecological significance is also obscure. Here, we conducted a quantitative evaluation of contact responses from closely related species of plasmodium to clarify the range of allorecognition behaviors in Myxomycetes. Behavioral assays demonstrated that allorecognition behaviors are specifically observed within individuals of the same species, indicating that these behaviors are a phenomenon unique to intraspecies interactions. Myxomycetes allorecognition is an extremely narrow and inward-focused behavior, suggesting for a highly specialized mechanism.
PubMed: 38912557
DOI: 10.1242/bio.060358 -
Protein and Peptide Letters Jun 2024Malaria caused by Plasmodium falciparum (Pf) is an illness that contributes significantly to the global health burden. Pf makes significant alterations to the host cell...
Malaria caused by Plasmodium falciparum (Pf) is an illness that contributes significantly to the global health burden. Pf makes significant alterations to the host cell to meet its metabolic demands and escape the immune response of the host. These include the export of a large number of parasite proteins to the infected Red Blood Cells (iRBC). Variable Surface Antigens (VSAs), which are highly polymorphic protein families with important roles in immune evasion, form an important component of the exported proteins. A total of five protein families constitute the VSAs, viz. PfEMP1 (Pf erythrocyte membrane protein 1), RIFIN (repetitive interspersed family), STEVOR (sub-telomeric open reading frame), SURFIN (surface-associated interspersed gene family), and PfMC-2TM (Pf Maurer's cleft two transmembrane). With orthologues present in various simian-infecting species, VSAs take up a variety of domain topologies and organizational structures while exhibiting differential expressions throughout the parasite life cycle. Their expression varies across clinical isolates and laboratory strains, which suggests their crucial role in host cell survival and defense. Members of VSAs are reported to contribute significantly to disease pathogenesis through immune evasion processes like cytoadherence, iRBC sequestration in the host vasculature, rosetting, reduced erythrocyte deformability, and direct immunosuppression. In this study, we have gathered information on various aspects of VSAs, like their orthologues, domain architecture, surface topology, functions and interactions, and three-dimensional structures, while emphasizing discoveries in the field. Considering the vast repertoire of Plasmodial VSAs with new emergent functions, a lot remains unknown about these families and, hence, malaria biology.
PubMed: 38910420
DOI: 10.2174/0109298665298567240530170924 -
Trends in Parasitology Jun 2024Small-Saunders et al. uncovered a new facet of artemisinin resistance in Plasmodium in which parasites use a previously underexplored arm of stress response mechanisms....
Small-Saunders et al. uncovered a new facet of artemisinin resistance in Plasmodium in which parasites use a previously underexplored arm of stress response mechanisms. Through altered epitranscriptomic modifications on tRNA, changed translation patterns adapt resistant cells to facilitate entry into a quiescent-like state which provides the parasite an escape from many drugs.
PubMed: 38910099
DOI: 10.1016/j.pt.2024.06.004