-
International Journal For Parasitology.... Apr 2021Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax, the most geographically widespread yet neglected human... (Review)
Review
Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax, the most geographically widespread yet neglected human malaria parasite. Endemic countries are expected to assess regularly the therapeutic efficacy of antimalarial drugs in use in order to adjust their malaria treatment policies, but proper funding and trained human resources are often lacking to execute relatively complex and expensive clinical studies, ideally complemented by ex vivo assays of drug resistance. Here we review the challenges for assessing in vivo P. vivax responses to commonly used antimalarials, especially chloroquine and primaquine, in the presence of confounding factors such as variable drug absorption, metabolism and interaction, and the risk of new infections following successful radical cure. We introduce a simple modeling approach to quantify the relative contribution of relapses and new infections to recurring parasitemias in clinical studies of hypnozoitocides. Finally, we examine recent methodological advances that may render ex vivo assays more practical and widely used to confirm P. vivax drug resistance phenotypes in endemic settings and review current approaches to the development of robust genetic markers for monitoring chloroquine resistance in P. vivax populations.
Topics: Antimalarials; Chloroquine; Humans; Malaria, Vivax; Plasmodium vivax; Primaquine
PubMed: 33360105
DOI: 10.1016/j.ijpddr.2020.12.001 -
Annual Review of Microbiology Oct 2021is the most widespread human malaria parasite, in part because it can form latent liver stages known as hypnozoites after transmission by female anopheline mosquitoes... (Review)
Review
is the most widespread human malaria parasite, in part because it can form latent liver stages known as hypnozoites after transmission by female anopheline mosquitoes to human hosts. These persistent stages can activate weeks, months, or even years after the primary clinical infection; replicate; and initiate relapses of blood stage infection, which causes disease and recurring transmission. Eliminating hypnozoites is a substantial obstacle for malaria treatment and eradication since the hypnozoite reservoir is undetectable and unaffected by most antimalarial drugs. Importantly, in some parts of the globe where malaria is endemic, as many as 90% of blood stage infections are thought to be relapses rather than primary infections, rendering the hypnozoite a major driver of epidemiology. Here, we review the biology of the hypnozoite and recent discoveries concerning this enigmatic parasite stage. We discuss treatment and prevention challenges, novel animal models to study hypnozoites and relapse, and hypotheses related to hypnozoite formation and activation.
Topics: Animals; Female; Liver; Malaria; Malaria, Vivax; Plasmodium vivax; Recurrence
PubMed: 34196569
DOI: 10.1146/annurev-micro-032421-061155 -
Immunological Reviews Jan 2020The efficient spread of malaria from infected humans to mosquitoes is a major challenge for malaria elimination initiatives. Gametocytes are the only Plasmodium life... (Review)
Review
The efficient spread of malaria from infected humans to mosquitoes is a major challenge for malaria elimination initiatives. Gametocytes are the only Plasmodium life stage infectious to mosquitoes. Here, we summarize evidence for naturally acquired anti-gametocyte immunity and the current state of transmission blocking vaccines (TBV). Although gametocytes are intra-erythrocytic when present in infected humans, developing Plasmodium falciparum gametocytes may express proteins on the surface of red blood cells that elicit immune responses in naturally exposed individuals. This immune response may reduce the burden of circulating gametocytes. For both P. falciparum and Plasmodium vivax, there is a solid evidence that antibodies against antigens present on the gametocyte surface, when co-ingested with gametocytes, can influence transmission to mosquitoes. Transmission reducing immunity, reducing the burden of infection in mosquitoes, is a well-acknowledged but poorly quantified phenomenon that forms the basis for the development of TBV. Transmission enhancing immunity, increasing the likelihood or intensity of transmission to mosquitoes, is more speculative in nature but is convincingly demonstrated for P. vivax. With the increased interest in malaria elimination, TBV and monoclonal antibodies have moved to the center stage of malaria vaccine development. Methodologies to prioritize and evaluate products are urgently needed.
Topics: Antibodies, Blocking; Antibodies, Protozoan; Host-Parasite Interactions; Humans; Immunity; Immunomodulation; Life Cycle Stages; Malaria Vaccines; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax
PubMed: 31840844
DOI: 10.1111/imr.12828 -
European Journal of Immunology Aug 2023Regulatory and effector cell responses to Plasmodium vivax, the most common human malaria parasite outside Africa, remain understudied in naturally infected populations....
Regulatory and effector cell responses to Plasmodium vivax, the most common human malaria parasite outside Africa, remain understudied in naturally infected populations. Here, we describe peripheral CD4 T- and B-cell populations during and shortly after an uncomplicated P. vivax infection in 38 continuously exposed adult Amazonians. Consistent with previous observations, we found an increased frequency in CD4 CD45RA CD25 FoxP3 T regulatory cells that express the inhibitory molecule CTLA-4 during the acute infection, with a sustained expansion of CD21 CD27 atypical memory cells within the CD19 B-cell compartment. Both Th1- and Th2-type subsets of CXCR5 ICOS PD-1 circulating T follicular helper (cTfh) cells, which are thought to contribute to antibody production, were induced during P. vivax infection, with a positive correlation between overall cTfh cell frequency and IgG antibody titers to the P. vivax blood-stage antigen MSP1 . We identified significant changes in cell populations that had not been described in human malaria, such as an increased frequency of CTLA-4 T follicular regulatory cells that antagonize Tfh cells, and a decreased frequency of circulating CD24 CD27 B regulatory cells in response to acute infection. In conclusion, we disclose a complex immunoregulatory network that is critical to understand how naturally acquired immunity develops in P. vivax malaria.
Topics: Adult; Humans; Plasmodium vivax; CTLA-4 Antigen; Malaria, Vivax; T-Lymphocytes, Helper-Inducer; CD4-Positive T-Lymphocytes
PubMed: 37160134
DOI: 10.1002/eji.202350372 -
Parasitology International Aug 2022
Topics: Humans; Malaria, Falciparum; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax
PubMed: 35526758
DOI: 10.1016/j.parint.2022.102594 -
Malaria Journal May 2021Loop-mediated isothermal amplification (LAMP) for malaria diagnosis at the point of care (POC) depends on the detection capacity of synthesized nucleic acids and the...
BACKGROUND
Loop-mediated isothermal amplification (LAMP) for malaria diagnosis at the point of care (POC) depends on the detection capacity of synthesized nucleic acids and the specificity of the amplification target. To improve malaria diagnosis, new colorimetric LAMP tests were developed using multicopy targets for Plasmodium vivax and Plasmodium falciparum detection.
METHODS
The cytochrome oxidase I (COX1) mitochondrial gene and the non-coding sequence Pvr47 for P. vivax, and the sub-telomeric sequence of erythrocyte membrane protein 1 (EMP1) and the non-coding sequence Pfr364 for P. falciparum were targeted to design new LAMP primers. The limit of detection (LOD) of each colorimetric LAMP was established and assessed with DNA extracted by mini spin column kit and the Boil & Spin method from 28 microscopy infections, 101 malaria submicroscopic infections detected by real-time PCR only, and 183 negatives infections by both microscopy and PCR.
RESULTS
The LODs for the colorimetric LAMPs were estimated between 2.4 to 3.7 parasites/µL of whole blood. For P. vivax detection, the colorimetric LAMP using the COX1 target showed a better performance than the Pvr47 target, whereas the Pfr364 target was the most specific for P. falciparum detection. All microscopic infections of P. vivax were detected by PvCOX1-LAMP using the mini spin column kit DNA extraction method and 81% (17/21) were detected using Boil & Spin sample preparation. Moreover, all microscopic infections of P. falciparum were detected by Pfr364-LAMP using both sample preparation methods. In total, PvCOX1-LAMP and Pfr364-LAMP detected 80.2% (81 samples) of the submicroscopic infections using the DNA extraction method by mini spin column kit, while 36.6% (37 samples) were detected using the Boil & Spin sample preparation method.
CONCLUSION
The colorimetric LAMPs with multicopy targets using the COX1 target for P. vivax and the Pfr364 for P. falciparum have a high potential to improve POC malaria diagnosis detecting a greater number of submicroscopic Plasmodium infections.
Topics: Colorimetry; Electron Transport Complex IV; Malaria, Falciparum; Malaria, Vivax; Molecular Diagnostic Techniques; Nucleic Acid Amplification Techniques; Plasmodium falciparum; Plasmodium vivax; Protozoan Proteins
PubMed: 34011373
DOI: 10.1186/s12936-021-03753-8 -
Frontiers in Cellular and Infection... 2021The development of genetic manipulation of in the 1980s was key to study malaria biology. Genetically modified parasites have been used to study several aspects of the... (Review)
Review
The development of genetic manipulation of in the 1980s was key to study malaria biology. Genetically modified parasites have been used to study several aspects of the disease, such as red blood cell invasion, drug resistance mechanisms, gametocyte development and mosquito transmission. However, biological and genetic differences between and the other human malaria parasites make a poor model to study different species. The lack of robust systems of long-term culture of and the other human malaria parasites lagged the genetic manipulation of these species. Here we review the efforts to generate genetically modified non- human malaria parasites, and . Using models - infection of non-human primates such as rhesus macaques and saimiri monkeys - researchers were able to generate transgenic lines of , and . The development of long-term culture of in the 2000's, using rhesus and human red blood cells, created a platform to genetically manipulate non- malaria parasites. Recently, the use of CRISPR/Cas9 technology to genome edit provides another tool to non-falciparum malaria research, extending the possibilities and allowing researchers to study different aspects of the biology of these parasites and understand the differences between these species and .
Topics: Animals; Humans; Macaca mulatta; Malaria; Malaria, Vivax; Parasites; Plasmodium knowlesi; Plasmodium vivax
PubMed: 34527600
DOI: 10.3389/fcimb.2021.680460 -
Frontiers in Cellular and Infection... 2021The control and elimination of malaria caused by both represent a great challenge due to the biological aspects of the species. Gametocytes are the forms responsible...
The control and elimination of malaria caused by both represent a great challenge due to the biological aspects of the species. Gametocytes are the forms responsible for the transmission of the parasite to the vector and the search for new strategies for blocking transmission are essential in a scenario of control and elimination The challenges in this search in regard to mainly stem from the lack of a long-term culture and the limitation of studies of gametocytes. This study evaluated the viability and infectivity of gametocytes in short-term culture. The samples enriched in gametocytes using Percoll (i), using magnetic-activated cell sorting (MACS) (ii), and using non-enriched samples (iii) were evaluated. After the procedures, gametocytes were cultured in IMDM medium for up to 48 h. Cultured gametocytes were viable and infectious for up to 48 h, however differences in viability and infectivity were observed in the samples after 12 h of culture in relation to 0 h. Percoll-enriched samples were shown to be viable in culture for longer intervals than those purified using MACS. Gametocyte viability after enrichment procedures and short-term culture may provide new avenues in the development of methods for evaluating TB.
Topics: Humans; Malaria; Malaria, Vivax; Plasmodium falciparum; Plasmodium vivax
PubMed: 34141630
DOI: 10.3389/fcimb.2021.676276 -
Trends in Parasitology Jun 2020Trager and Jensen established a method for culturing Plasmodium falciparum, a breakthrough for malaria research worldwide. Since then, multiple attempts to establish... (Review)
Review
Trager and Jensen established a method for culturing Plasmodium falciparum, a breakthrough for malaria research worldwide. Since then, multiple attempts to establish Plasmodium vivax in continuous culture have failed. Unlike P. falciparum, which can invade all aged erythrocytes, P. vivax is restricted to reticulocytes. Thus, a constant supply of reticulocytes is considered critical for continuous P. vivax growth in vitro. A critical question remains why P. vivax selectively invades reticulocytes? What do reticulocytes offer to P. vivax that is not present in mature erythrocytes? One possibility is protection from oxidative stress by glucose-6-phosphate dehydrogenase (G6PD). Here, we also suggest supplements to the media and procedures that may reduce oxidative stress and, as a result, establish a system for the continuous culture of P. vivax.
Topics: Culture Techniques; Erythrocytes; Host-Parasite Interactions; Humans; Life Cycle Stages; Oxidative Stress; Plasmodium vivax; Reticulocytes
PubMed: 32360314
DOI: 10.1016/j.pt.2020.04.002 -
Malaria Journal May 2022The global malaria burden sometimes obscures that the genus Plasmodium comprises diverse clades with lineages that independently gave origin to the extant human... (Review)
Review
The global malaria burden sometimes obscures that the genus Plasmodium comprises diverse clades with lineages that independently gave origin to the extant human parasites. Indeed, the differences between the human malaria parasites were highlighted in the classical taxonomy by dividing them into two subgenera, the subgenus Plasmodium, which included all the human parasites but Plasmodium falciparum that was placed in its separate subgenus, Laverania. Here, the evolution of Plasmodium in primates will be discussed in terms of their species diversity and some of their distinct phenotypes, putative molecular adaptations, and host-parasite biocenosis. Thus, in addition to a current phylogeny using genome-level data, some specific molecular features will be discussed as examples of how these parasites have diverged. The two subgenera of malaria parasites found in primates, Plasmodium and Laverania, reflect extant monophyletic groups that originated in Africa. However, the subgenus Plasmodium involves species in Southeast Asia that were likely the result of adaptive radiation. Such events led to the Plasmodium vivax lineage. Although the Laverania species, including P. falciparum, has been considered to share "avian characteristics," molecular traits that were likely in the common ancestor of primate and avian parasites are sometimes kept in the Plasmodium subgenus while being lost in Laverania. Assessing how molecular traits in the primate malaria clades originated is a fundamental science problem that will likely provide new targets for interventions. However, given that the genus Plasmodium is paraphyletic (some descendant groups are in other genera), understanding the evolution of malaria parasites will benefit from studying "non-Plasmodium" Haemosporida.
Topics: Animals; Malaria; Malaria, Falciparum; Plasmodium; Plasmodium falciparum; Plasmodium vivax
PubMed: 35505356
DOI: 10.1186/s12936-022-04130-9