Malaria is a protozoan disease transmitted by the bite of the Anopheles mosquito. Among five species that can infect humans, Plasmodium falciparum is responsible for the most severe human malaria. ...Resistance of P. falciparum to chloroquine and pyrimethamine/sulfadoxine, conventionally used antimalarial drugs, is already widely distributed in many endemic areas. As a result, artemisinin-based combination therapies have been rapidly and widely adopted as first-line antimalarial treatments since the mid-2000s. Recent population and evolutionary genetic analyses have proven that the geographic origins of parasite lineages resistant to the conventional drugs are considerably limited. Almost all resistance emerged from either Southeast Asia or South America. The Greater Mekong subregion in Southeast Asia is probably the most alarming source of resistance, from which P. falciparum resistant to chloroquine and pyrimethamine/sulfadoxine dispersed to Africa. The emergence of artemisinin resistance has also recently been confirmed in the Greater Mekong. The WHO Global Malaria Programme has recently launched a “Global Plan for Artemisinin Resistance Containment,” which aims to prevent the spread of artemisinin resistance while also stopping the emergence of novel resistance. However, an inadequate understanding of a mechanism of artemisinin resistance and the lack of reliable genetic markers to monitor artemisinin resistance make it difficult to survey the spread of resistance. Elucidation of such markers would substantially contribute to the design of an effective policy for the containment of artemisinin resistance.
Abstract Worldwide spread of Plasmodium falciparum drug resistance to conventional antimalarials, chloroquine and sulfadoxine/pyrimethamine, has been imposing a serious public health problem in many ...endemic regions. Recent discovery of drug resistance-associated genes, pfcrt , pfmdr1 , dhfr , and dhps , and applications of microsatellite markers flanking the genes have revealed the evolution of parasite resistance to these antimalarials and the geographical spread of drug resistance. Here, we review our recent knowledge of the evolution and spread of parasite resistance to chloroquine and sulfadoxine/pyrimethamine. In both antimalarials, resistance appears to be largely explained by the invasion of limited resistant lineages to many endemic regions. However, multiple, indigenous evolutionary origins of resistant lineages have also been demonstrated. Further molecular evolutionary and population genetic approaches will greatly facilitate our understanding of the evolution and spread of parasite drug resistance, and will contribute to developing strategies for better control of malaria.
Although it is known that malaria parasites proliferate in the midgut of mosquito vector, their detailed behaviors, from gamete maturation to formation of next generation sporozoite, have not been ...fully understood at cellular or molecular level. This is mainly attributed to technical difficulties of dissection and whole-mount observation, of delicate and opaque mosquito body contents. In addition, blood pigment surrounding parasites immediately after blood meal also complicates tracing mosquito-stage parasites. Recent revolutionary studies have overcome such negative factors in tissue observation by clearing organisms. CUBIC reagents succeeded to remove both light scattering and blood pigment from various mouse tissues, and to whole-organ image fluorescence-labeled cell structures. In this study, we utilized the advanced version of CUBIC technology and high sensitivity fluorescent markers for see-through observation of mosquito vector after engulfment of rodent malaria parasites to clarify their behaviors during mosquito stage. As a result, we succeeded to visualize oocysts, sporozoites, female gametes and ookinetes in the mosquito bodies without any dissection.
Abstract
Background
The C580Y mutation in the
Plasmodium falciparum kelch13
gene is the most commonly observed variant in artemisinin-resistant isolates in the Greater Mekong Subregion (GMS). Until ...2017, it had not been identified outside the GMS, except for Guyana/Amazonia. In 2017, three parasites carrying the C580Y mutation were identified in Papua New Guinea (PNG). As the C580Y allele rapidly spread in the GMS, there is concern that this mutant is now spreading in PNG.
Methods
In 2020, a cross-sectional survey was conducted at two clinics in Wewak, PNG. Symptomatic patients infected with
P. falciparum
were treated with artemether plus lumefantrine following a national treatment policy. Blood samples were obtained before treatment, and polymorphisms in
kelch13
,
pfcrt
, and
pfmdr1
were determined. Parasite positivity was examined on day 3. The results were compared with those of previous studies conducted in 2002, 2003, and 2016–2018.
Results
A total of 94 patients were included in this analysis. The proportion of C580Y was significantly increased (2.2% in 2017, 5.7% in 2018, and 6.4% in 2020; p = 4.2 × 10
–3
). A significant upward trend was observed in the wild-type proportion for
pfcrt
(1.9% in 2016 to 46.7% in 2020; p = 8.9 × 10
–16
) and
pfmdr1
(59.5% in 2016 to 91.4% in 2020; p = 2.3 × 10
–6
). Among 27 patients successfully followed on day 3, including three with C580Y infections, none showed positive parasitaemia.
Conclusions
Under the conditions of significant increases in
pfcrt
K76 and
pfmdr1
N86 alleles in PNG, the increase in
kelch13
C580Y mutants may be a warning indicator of the emergence of parasites resistant to the currently used first-line treatment regimen of artemether plus lumefantrine. Therefore, nationwide surveillance of molecular markers for drug resistance and assessment of its therapeutic effects are important.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because ≈90% of malaria cases occur in Africa, emergence of artemisinin-resistant Plasmodium falciparum in Africa poses a serious public health threat. To assess emergence of artemisinin-resistant ...parasites in Uganda during 2014-2016, we used the recently developed ex vivo ring-stage survival assay, which estimates ring-stage-specific P. falciparum susceptibility to artemisinin. We conducted 4 cross-sectional surveys to assess artemisinin sensitivity in Gulu, Uganda. Among 194 isolates, survival rates (ratio of viable drug-exposed parasites to drug-nonexposed controls) were high (>10%) for 4 isolates. Similar rates have been closely associated with delayed parasite clearance after drug treatment and are considered to be a proxy for the artemisinin-resistant phenotype. Of these, the PfKelch13 mutation was observed in only 1 isolate, A675V. Population genetics analysis suggested that these possibly artemisinin-resistant isolates originated in Africa. Large-scale surveillance of possibly artemisinin-resistant parasites in Africa would provide useful information about treatment outcomes and help regional malaria control.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
More than 17% of worldwide infectious diseases are caused by vector-borne diseases. A numerous number of living organisms can act as a vector. In Japan, tick-borne diseases are particularly important ...because these diseases occasionally lead to a fatal clinical outcome. Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified tick-borne disease caused by phlebovirus in the Bunyaviridae family. Most SFTS patients have been observed in China, South Korea and Japan. SFTS was first identified in 2013 in Japan and reached to 310 cases by 2017 with a high case-fatality rate (7.8%). SFTS transmission cycles between ticks and wild animals have been already established throughout Japan. This review outlines the current epidemiology of SFTS in Japan, with an emphasis on ecology of vector and animals and clinical features of Japanese patients.
The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there ...is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Artemisinin-resistant Plasmodium falciparum is spreading in Southeast Asia and Africa. In vivo susceptibility to artemisinin is studied by looking at the rate of decline of ...peripheral parasitemia (parasite clearance half-life). However, parasites that are adhered/sequestered to the endothelium and undetectable in the peripheral blood are not considered in the estimation of parasite clearance. Here, we evaluated the influence of sequestration on in vivo artemisinin efficacy in Uganda, where artemisinin resistance is spreading.
Methods
We analyzed 133 patients with P. falciparum malaria included in an in vivo study on artemisinin efficacy in northern Uganda in 2018 and 2019. The parasite clearance half-life was estimated from peripheral parasitemia after artemisinin monotherapy. P. falciparum histidine-rich protein 2 (PfHRP2) was measured in pretreatment plasma. The number of sequestered parasites was estimated from PfHRP2 concentration and peripheral parasitemia.
Results
The estimated number of sequestered parasites per plasma volume ranged from 0 to 2 564 000/μL. Inflammation, thrombocytopenia, and dyslipidemia were significantly associated with sequestration independent of peripheral parasitemia. The median parasite clearance half-lives were 1.65 hours in patients infected with Pfkelch13 wild-type parasites (n = 104) and 3.95 hours in those with A675V artemisinin-resistant mutant (n = 18). In the multivariable model for the wild-type population, 1 000 000/μL of sequestered parasites were estimated to delay parasite clearance by 16.8% (95% confidence interval, 5.1%–28.5%), although it was not clear in the A675V population.
Conclusions
In patients with P. falciparum malaria without artemisinin-resistant mutations, intensive sequestration delays parasite clearance after treatment, which may contribute to reduced artemisinin efficacy.
Mature Plasmodium falciparum parasites are rarely found in the peripheral blood because they are sequestered and attached to the endothelium. We demonstrated that intensive sequestration was associated with a delay in parasite clearance after artemisinin-based treatment, independent of artemisinin-resistant mutations
Understanding Plasmodium falciparum population diversity and transmission dynamics provides information on the intensity of malaria transmission, which is needed for assessing malaria control ...interventions. This study aimed to determine P. falciparum allelic diversity and multiplicity of infection (MOI) among asymptomatic and symptomatic school-age children in Kinshasa Province, Democratic Republic of Congo (DRC).
A total of 438 DNA samples (248 asymptomatic and 190 symptomatic) were characterized by nested PCR and genotyping the polymorphic regions of pfmsp1 block 2 and pfmsp2 block 3.
Nine allele types were observed in pfmsp1 block2. The K1-type allele was predominant with 78% (229/293) prevalence, followed by the MAD20-type allele (52%, 152/293) and RO33-type allele (44%, 129/293). Twelve alleles were detected in pfmsp2, and the 3D7-type allele was the most frequent with 84% (256/304) prevalence, followed by the FC27-type allele (66%, 201/304). Polyclonal infections were detected in 63% (95% CI 56, 69) of the samples, and the MOI (SD) was 1.99 (0.97) in P. falciparum single-species infections. MOIs significantly increased in P. falciparum isolates from symptomatic parasite carriers compared with asymptomatic carriers (2.24 versus 1.69, adjusted b: 0.36, (95% CI 0.01, 0.72), p = 0.046) and parasitaemia > 10,000 parasites/µL compared to parasitaemia < 5000 parasites/µL (2.68 versus 1.63, adjusted b: 0.89, (95% CI 0.46, 1.25), p < 0.001).
This survey showed low allelic diversity and MOI of P. falciparum, which reflects a moderate intensity of malaria transmission in the study areas. MOIs were more likely to be common in symptomatic infections and increased with the parasitaemia level. Further studies in different transmission zones are needed to understand the epidemiology and parasite complexity in the DRC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Plasmodium falciparum is the main agent of malaria, one of the major human infectious diseases affecting millions of people worldwide. The genetic diversity of P. falciparum populations is ...an essential factor in the parasite's ability to adapt to changes in its environment, enabling the development of drug resistance and the evasion from the host immune system through antigenic variation. Therefore, characterizing these patterns and understanding the main drivers of the pathogen's genetic diversity can provide useful inputs for informing control strategies. In this paper, we review the pioneering work led by Professor Kazuyuki Tanabe on the genetic diversity of P. falciparum populations. In a first part, we recall basic results from population genetics for quantifying within-population genetic diversity, and discuss the main mechanisms driving this diversity. Then, we show how these approaches have been used for reconstructing the historical spread of malaria worldwide, and how current patterns of genetic diversity suggest that the pathogen followed our ancestors in their journey out of Africa. Because these results are robust to different types of genetic markers, they provide a baseline for predicting the pathogen's diversity in unsampled populations, and some useful elements for predicting vaccine efficacy and informing malaria control strategies.
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