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Malaria Journal Dec 2023Plasmodium vivax has been more resistant to various control measures than Plasmodium falciparum malaria because of its greater transmissibility and ability to produce...
BACKGROUND
Plasmodium vivax has been more resistant to various control measures than Plasmodium falciparum malaria because of its greater transmissibility and ability to produce latent parasite forms. Therefore, developing P. vivax vaccines and therapeutic monoclonal antibodies (humAbs) remains a high priority. The Duffy antigen receptor for chemokines (DARC) expressed on erythrocytes is central to P. vivax invasion of reticulocytes. P. vivax expresses a Duffy binding protein (PvDBP) on merozoites, a DARC ligand, and the DARC: PvDBP interaction is critical for P. vivax blood stage malaria. Therefore, PvDBP is a leading vaccine candidate for P. vivax and a target for therapeutic human monoclonal antibodies (humAbs).
METHODS
Here, the functional activity of humAbs derived from naturally exposed and vaccinated individuals are compared for the first time using easily cultured Plasmodium knowlesi (P. knowlesi) that had been genetically modified to replace its endogenous PkDBP orthologue with PvDBP to create a transgenic parasite, PkPvDBPOR. This transgenic parasite requires DARC to invade human erythrocytes but is not reticulocyte restricted. This model was used to evaluate the invasion inhibition potential of 12 humAbs (9 naturally acquired; 3 vaccine-induced) targeting PvDBP individually and in combinations using growth inhibition assays (GIAs).
RESULTS
The PvDBP-specific humAbs demonstrated 70-100% inhibition of PkPvDBPOR invasion with the IC values ranging from 51 to 338 µg/mL for the 9 naturally acquired (NA) humAbs and 33 to 99 µg/ml for the 3 vaccine-induced (VI) humAbs. To evaluate antagonistic, additive, or synergistic effects, six pairwise combinations were performed using select humAbs. Of these combinations tested, one NA/NA (099100/094083) combination demonstrated relatively strong additive inhibition between 10 and 100 µg/mL; all combinations of NA and VI humAbs showed additive inhibition at concentrations below 25 µg/mL and antagonism at higher concentrations. None of the humAb combinations showed synergy. Invasion inhibition efficacy by some mAbs shown with PkPvDBPOR was closely replicated using P. vivax clinical isolates.
CONCLUSION
The PkPvDBPOR transgenic model is a robust surrogate of P. vivax to assess invasion and growth inhibition of human monoclonal Abs recognizing PvDBP individually and in combination. There was no synergistic interaction for growth inhibition with the humAbs tested here that target different epitopes or subdomains of PvDBP, suggesting little benefit in clinical trials using combinations of these humAbs.
Topics: Animals; Humans; Plasmodium vivax; Plasmodium knowlesi; Antibodies, Protozoan; Antigens, Protozoan; Protozoan Proteins; Malaria, Vivax; Erythrocytes; Animals, Genetically Modified; Malaria Vaccines; Duffy Blood-Group System
PubMed: 38049801
DOI: 10.1186/s12936-023-04766-1 -
Cell Reports. Medicine Jun 2022Serological markers are a promising tool for surveillance and targeted interventions for Plasmodium vivax malaria. P. vivax is closely related to the zoonotic parasite...
Serological markers are a promising tool for surveillance and targeted interventions for Plasmodium vivax malaria. P. vivax is closely related to the zoonotic parasite P. knowlesi, which also infects humans. P. vivax and P. knowlesi are co-endemic across much of South East Asia, making it important to design serological markers that minimize cross-reactivity in this region. To determine the degree of IgG cross-reactivity against a panel of P. vivax serological markers, we assayed samples from human patients with P. knowlesi malaria. IgG antibody reactivity is high against P. vivax proteins with high sequence identity with their P. knowlesi ortholog. IgG reactivity peaks at 7 days post-P. knowlesi infection and is short-lived, with minimal responses 1 year post-infection. We designed a panel of eight P. vivax proteins with low levels of cross-reactivity with P. knowlesi. This panel can accurately classify recent P. vivax infections while reducing misclassification of recent P. knowlesi infections.
Topics: Humans; Immunoglobulin G; Malaria; Malaria, Vivax; Plasmodium knowlesi; Plasmodium vivax
PubMed: 35732155
DOI: 10.1016/j.xcrm.2022.100662 -
Emerging Infectious Diseases Feb 2021Among 1,180 symptomatic malaria patients, 9 (0.76%) infected with Plasmodium cynomolgi were co-infected with P. vivax (n = 7), P. falciparum (n = 1), or P. vivax and P....
Among 1,180 symptomatic malaria patients, 9 (0.76%) infected with Plasmodium cynomolgi were co-infected with P. vivax (n = 7), P. falciparum (n = 1), or P. vivax and P. knowlesi (n = 1). Patients were from Tak, Chanthaburi, Ubon Ratchathani, Yala, and Narathiwat Provinces, suggesting P. cynomolgi is widespread in this country.
Topics: Coinfection; Humans; Malaria; Malaria, Vivax; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium knowlesi; Plasmodium vivax; Thailand
PubMed: 33496236
DOI: 10.3201/eid2702.191660 -
Frontiers in Veterinary Science 2023The imminent risk of zoonoses of non-human malaria parasites is not far from reality in India, as has been observed in the case of Plasmodium knowlesi (Pk), and so is...
INTRODUCTION
The imminent risk of zoonoses of non-human malaria parasites is not far from reality in India, as has been observed in the case of Plasmodium knowlesi (Pk), and so is possible with (Pc), already reported from South East Asian countries. Therefore, a novel multiplex qPCR assay was developed and evaluated for detection of non-human malaria parasites- Pk and Pc in populations at risk.
METHODS
The qPCR primers were designed in-house with fluorescence labeled probes (HEX for Pk and FAM for Pc). DNA samples of Pk and Pc were used as templates and further the qPCR assay was evaluated in 250 symptomatic and asymptomatic suspected human blood samples from malaria endemic areas of North Eastern states of India.
RESULTS
The qPCR assay successfully amplified the target 18S rRNA gene segment from Pk and Pc and was highly specific for Pk and Pc parasites only, as no cross reactivity was observed with (Pf), (Pv), (Pm), and (Po). Standard curves were generated to estimate the limit of detection (LOD) of Pk and Pc parasites DNA (0.00275 & 0.075 ng/μl, respectively). Due to COVID-19 pandemic situation during 2020-21, the sample accessibility was difficult, however, we managed to collect 250 samples. The samples were tested for Pf and Pv using conventional PCR- 14 Pf and 11 Pv infections were observed, but no Pk and Pc infections were detected. For Pk infections, previously reported conventional PCR was also performed, but no Pk infection was detected.
DISCUSSION
The multiplex qPCR assay was observed to be robust, quick, cost-effective and highly sensitive as compared to the currently available conventional PCR methods. Further validation of the multiplex qPCR assay in field setting is desirable, especially from the high-risk populations. We anticipate that the multiplex qPCR assay would prove to be a useful tool in mass screening and surveillance programs for detection of non-human malaria parasites toward the control and elimination of malaria from India by 2030.
PubMed: 36777671
DOI: 10.3389/fvets.2023.1127273 -
Microorganisms Feb 2021Vector-borne parasitic infectious diseases are important causes of morbidity and mortality globally. Malaria is one of the most common vector-borne parasitic infection... (Review)
Review
Vector-borne parasitic infectious diseases are important causes of morbidity and mortality globally. Malaria is one of the most common vector-borne parasitic infection and is caused by five species, namely and . Epidemiologically, differences in the patterns of malaria cases, causative agent, disease severity, antimicrobial resistance, and mortality exist across diverse geographical regions. The world witnessed 229 million malaria cases which resulted in 409,000 deaths in 2019 alone. Although malaria cases are reported from 87 countries globally, Africa bears the brunt of these infections and deaths as nearly 94% of total malaria cases and deaths occur in this continent, particularly in sub-Saharan Africa. Most of the Middle East Region countries are malaria-free as no indigenous cases of infection have been described in recent years. However, imported cases of malaria continue to occur as some of these countries. Indeed, the six Gulf Cooperation Council (GCC) countries have large expatriate population originating from malaria endemic countries. In this review, the current status and epidemiology of malaria in the Middle East Region countries and other malaria-endemic countries that are home to a large migrant workforce being employed in Middle East Region countries are discussed.
PubMed: 33572053
DOI: 10.3390/microorganisms9020338 -
Frontiers in Cellular and Infection... 2021Regulating the number of progeny generated by replicative cell cycles is critical for any organism to best adapt to its environment. Classically, the decision whether to... (Review)
Review
Regulating the number of progeny generated by replicative cell cycles is critical for any organism to best adapt to its environment. Classically, the decision whether to divide further is made after cell division is completed by cytokinesis and can be triggered by intrinsic or extrinsic factors. Contrarily, cell cycles of some species, such as the malaria-causing parasites, go through multinucleated cell stages. Hence, their number of progeny is determined prior to the completion of cell division. This should fundamentally affect how the process is regulated and raises questions about advantages and challenges of multinucleation in eukaryotes. Throughout their life cycle spp. parasites undergo four phases of extensive proliferation, which differ over three orders of magnitude in the amount of daughter cells that are produced by a single progenitor. Even during the asexual blood stage proliferation parasites can produce very variable numbers of progeny within one replicative cycle. Here, we review the few factors that have been shown to affect those numbers. We further provide a comparative quantification of merozoite numbers in several and parasite strains, and we discuss the general processes that may regulate progeny number in the context of host-parasite interactions. Finally, we provide a perspective of the critical knowledge gaps hindering our understanding of the molecular mechanisms underlying this exciting and atypical mode of parasite multiplication.
Topics: Animals; Cytokinesis; Erythrocytes; Malaria, Falciparum; Merozoites; Parasites; Plasmodium falciparum
PubMed: 34026661
DOI: 10.3389/fcimb.2021.658616 -
Scientific Reports Sep 2021Plasmodium knowlesi, a model malaria parasite, is responsible for a significant portion of zoonotic malaria cases in Southeast Asia and must be controlled to avoid...
Plasmodium knowlesi, a model malaria parasite, is responsible for a significant portion of zoonotic malaria cases in Southeast Asia and must be controlled to avoid disease severity and fatalities. However, little is known about the host-parasite interactions and molecular mechanisms in play during the course of P. knowlesi malaria infections, which also may be relevant across Plasmodium species. Here we contrast P. knowlesi sporozoite-initiated infections in Macaca mulatta and Macaca fascicularis using whole blood RNA-sequencing and transcriptomic analysis. These macaque hosts are evolutionarily close, yet malaria-naïve M. mulatta will succumb to blood-stage infection without treatment, whereas malaria-naïve M. fascicularis controls parasitemia without treatment. This comparative analysis reveals transcriptomic differences as early as the liver phase of infection, in the form of signaling pathways that are activated in M. fascicularis, but not M. mulatta. Additionally, while most immune responses are initially similar during the acute stage of the blood infection, significant differences arise subsequently. The observed differences point to prolonged inflammation and anti-inflammatory effects of IL10 in M. mulatta, while M. fascicularis undergoes a transcriptional makeover towards cell proliferation, consistent with its recovery. Together, these findings suggest that timely detection of P. knowlesi in M. fascicularis, coupled with control of inflammation while initiating the replenishment of key cell populations, helps contain the infection. Overall, this study points to specific genes and pathways that could be investigated as a basis for new drug targets that support recovery from acute malaria.
Topics: Animals; Biological Evolution; Biomarkers; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Host-Parasite Interactions; Macaca fascicularis; Macaca mulatta; Malaria; Molecular Sequence Annotation; Monkey Diseases; Plasmodium knowlesi; Signal Transduction; Species Specificity; Transcriptome
PubMed: 34593836
DOI: 10.1038/s41598-021-98024-6 -
Scientific Reports Apr 2021Plasmodium knowlesi is the main cause of malaria in Sarawak, where studies on vectors of P. knowlesi have been conducted in only two districts. Anopheles balabacensis...
Plasmodium knowlesi is the main cause of malaria in Sarawak, where studies on vectors of P. knowlesi have been conducted in only two districts. Anopheles balabacensis and An. donaldi were incriminated as vectors in Lawas and An. latens in Kapit. We studied a third location in Sarawak, Betong, where of 2169 mosquitoes collected over 36 days using human-landing catches, 169 (7.8%) were Anopheles spp. PCR and phylogenetic analyses identified P. knowlesi and/or P. cynomolgi, P. fieldi, P. inui, P. coatneyi and possibly novel Plasmodium spp. in salivary glands of An. latens and An. introlatus from the Leucosphyrus Group and in An. collessi and An. roperi from the Umbrosus Group. Phylogenetic analyses of cytochrome oxidase subunit I sequences indicated three P. knowlesi-positive An. introlatus had been misidentified morphologically as An. latens, while An. collessi and An. roperi could not be delineated using the region sequenced. Almost all vectors from the Leucosphyrus Group were biting after 1800 h but those belonging to the Umbrosus Group were also biting between 0700 and 1100 h. Our study incriminated new vectors of knowlesi malaria in Sarawak and underscores the importance of including entomological studies during the daytime to obtain a comprehensive understanding of the transmission dynamics of malaria.
Topics: Animals; Borneo; DNA; Macaca fascicularis; Malaysia; Mosquito Vectors; Phylogeny; Plasmodium; Plasmodium knowlesi; Species Specificity
PubMed: 33833272
DOI: 10.1038/s41598-021-86107-3 -
BMC Research Notes Jan 2020Acute kidney injury (AKI) is a frequent presentation in malaria infections. Several cases of AKI that are accompanied by clinical symptoms of malaria infection, such as...
OBJECTIVE
Acute kidney injury (AKI) is a frequent presentation in malaria infections. Several cases of AKI that are accompanied by clinical symptoms of malaria infection, such as fever, nausea, respiratory distress, and anemia remain undiagnosed due to challenges in accurate diagnosis using peripheral blood microscopy and rapid diagnostic tests that are currently used in clinical settings. This is particularly true for P. vivax and P. knowlesi infections. As a result, these patients are not able to receive anti-malarial therapy in a timely manner. The objective of the present study was to investigate if patients presenting with AKI harbored any of the five human Plasmodium species (P. falciparum, P. vivax, P. knowlesi, P. malariae, and P. ovale) within their renal tissues.
RESULTS
We found that renal biopsies from malaria associated AKI patients harbor the human malaria parasites P. falciparum, P. vivax and P. knowlesi as mono- and mixed species infections. Presence of microvascular injury in a majority of the malaria associated AKI cases suggested vascular involvement of P. vivax and P. knowlesi. This research note also highlights P. knowlesi as an emerging pathogen in the Indian subcontinent.
Topics: Acute Kidney Injury; Biopsy; Case-Control Studies; India; Kidney; Malaria; Microscopy; Plasmodium; Plasmodium falciparum; Plasmodium knowlesi; Plasmodium vivax; Retrospective Studies
PubMed: 31959229
DOI: 10.1186/s13104-020-4900-1 -
Spatial analyses of Plasmodium knowlesi vectors with reference to control interventions in Malaysia.Parasites & Vectors Oct 2023Malaria parasites such as Plasmodium knowlesi, P. inui, and P. cynomolgi are spread from macaques to humans through the Leucosphyrus Group of Anopheles mosquitoes. It is...
BACKGROUND
Malaria parasites such as Plasmodium knowlesi, P. inui, and P. cynomolgi are spread from macaques to humans through the Leucosphyrus Group of Anopheles mosquitoes. It is crucial to know the distribution of these vectors to implement effective control measures for malaria elimination. Plasmodium knowlesi is the most predominant zoonotic malaria parasite infecting humans in Malaysia.
METHODS
Vector data from various sources were used to create distribution maps from 1957 to 2021. A predictive statistical model utilizing logistic regression was developed using significant environmental factors. Interpolation maps were created using the inverse distance weighted (IDW) method and overlaid with the corresponding environmental variables.
RESULTS
Based on the IDW analysis, high vector abundances were found in the southwestern part of Sarawak, the northern region of Pahang and the northwestern part of Sabah. However, most parts of Johor, Sabah, Perlis, Penang, Kelantan and Terengganu had low vector abundance. The accuracy test indicated that the model predicted sampling and non-sampling areas with 75.3% overall accuracy. The selected environmental variables were entered into the regression model based on their significant values. In addition to the presence of water bodies, elevation, temperature, forest loss and forest cover were included in the final model since these were significantly correlated. Anopheles mosquitoes were mainly distributed in Peninsular Malaysia (Titiwangsa range, central and northern parts), Sabah (Kudat, West Coast, Interior and Tawau division) and Sarawak (Kapit, Miri, and Limbang). The predicted Anopheles mosquito density was lower in the southern part of Peninsular Malaysia, the Sandakan Division of Sabah and the western region of Sarawak.
CONCLUSION
The study offers insight into the distribution of the Leucosphyrus Group of Anopheles mosquitoes in Malaysia. Additionally, the accompanying predictive vector map correlates well with cases of P. knowlesi malaria. This research is crucial in informing and supporting future efforts by healthcare professionals to develop effective malaria control interventions.
Topics: Humans; Animals; Malaysia; Plasmodium knowlesi; Mosquito Vectors; Malaria; Macaca; Anopheles; Spatial Analysis
PubMed: 37814287
DOI: 10.1186/s13071-023-05984-x