scholarly journals Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?

2021 ◽  
Author(s):  
Moses Okpeku
Keyword(s):  
Drug Resistance ◽  
Malaria Elimination ◽  
Malaria Parasite ◽  
Disease Burden ◽  
Drug Application ◽  
African Region ◽  
Malaria Parasites ◽  
Sub Saharan ◽  
Host Development

Malaria is a global disease of importance, especially in the sub-Saharan African region, where malaria accounts for great losses economically and to life. Fight to eliminate this disease has resulted in reduced disease burden in many places where the diseases is endemic. Elimination strategies in most places is focus on the use of treated nets and drug application. Exposure of malaria parasites to anti-malaria drugs have led to the evolution of drug resistance in both parasites and host. Development of drug resistance vary but, studies on adaptive drug resistance has implications and consequences. Our knowledge of this consequences are limited but important for the pursuit of an uninterrupted malaria elimination agenda. This chapter draws our attention to this risks and recommends interventions.

scholarly journals Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Ann M. Guggisberg ◽  
Philip M. Frasse ◽  
Andrew J. Jezewski ◽  
Natasha M. Kafai ◽  
Aakash Y. Gandhi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Malaria Parasite ◽  
Glycolytic Enzyme ◽  
Genetic Mechanism ◽  
Growth Defect ◽  
Malaria Parasites ◽  
Content Type ◽  
Metabolic Plasticity ◽  
Glycolytic Intermediates ◽  
Metabolic Regulators

ABSTRACT In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation. IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.

scholarly journals Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance

2015 ◽  
Vol 212 (6) ◽  
pp. 893-903 ◽  
Author(s):  
Jing-wen Lin ◽  
Roberta Spaccapelo ◽  
Evelin Schwarzer ◽  
Mohammed Sajid ◽  
Takeshi Annoura ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Malaria Parasite ◽  
Chloroquine Resistance ◽  
Malaria Parasites ◽  
Human Malaria ◽  
Complete Development

Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes.

scholarly journals The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance

2008 ◽  
Vol 7 (1) ◽  
Author(s):  
Jean-Pierre Van geertruyden ◽  
Joris Menten ◽  
Robert Colebunders ◽  
Eline Korenromp ◽  
Umberto D'Alessandro
Keyword(s):  
Drug Resistance ◽  
Antimalarial Drug ◽  
Malaria Parasite ◽  
Sub Saharan Africa ◽  
Antimalarial Drug Resistance ◽  
Sub Saharan ◽  
The Impact ◽  
Hiv 1

scholarly journals Molecular Dynamics Simulation and Analysis of some Ligands on Var2csA Target

2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Ifeanyichukwu Okeke
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Molecular Dynamics Simulation ◽  
Neonatal Outcomes ◽  
Sub Saharan Africa ◽  
Dynamics Simulation ◽  
Malaria Parasites ◽  
Adjunct Treatment ◽  
Malaria During Pregnancy ◽  
Sub Saharan

Prevalence of malaria during pregnancy and the spate of drug resistance by malaria parasites have constantly impacted maternal, perinatal and neonatal outcomes, especially in sub-Saharan Africa. Inhibiting binding; or displacement of bound infected erythrocytes from the placenta as an adjunct treatment or vaccine for malaria was considered an option towards ending pregnancy associated malaria in this study.

scholarly journals Can Mixed Parasite Infections Thwart Targeted Malaria Elimination Program in India?

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Upasana Shyamsunder Singh ◽  
Nisha Siwal ◽  
Veena Pande ◽  
Aparup Das
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Elimination ◽  
Disease Burden ◽  
Parasitic Infections ◽  
Published Data ◽  
Diagnostic Assay ◽  
Mixed Species ◽  
Malaria Parasites ◽  
Human Malaria ◽  
Parasite Infections

India is highly endemic to malaria with prevalence of all five species of human malaria parasites of Plasmodium genus. India is set for malaria elimination by 2030. Since cases of mixed Plasmodium species infections remain usually undetected but cause huge disease burden, in order to understand the distributional prevalence of both monospecies infections and mixed species infections in India, we collated published data on the differential infection incidences of the five different malaria parasites based on PCR diagnostic assay. About 11% of total cases were due to mixed species infection. Among several interesting observations on both single and mixed parasitic infections, incidences of Plasmodium falciparum monoinfection were found to be significantly higher than P. vivax monoinfection. Also, P. malariae seems to be emerging as a potential malaria threat in India. Putting all the facts together, it appears that the dream of achieving malaria elimination in India will not be completely successful without dealing with mixed species infection.

scholarly journals Suppression of drug resistance reveals a genetic mechanism of metabolic plasticity in malaria parasites

2017 ◽  
Author(s):  
Ann M. Guggisberg ◽  
Philip M. Frasse ◽  
Andrew J. Jezewski ◽  
Natasha M. Kafai ◽  
Aakash Y. Gandhi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Malaria Parasite ◽  
Glycolytic Enzyme ◽  
Genetic Mechanism ◽  
Growth Defect ◽  
Loss Of Function ◽  
Malaria Parasites ◽  
Metabolic Plasticity ◽  
Glycolytic Intermediates ◽  
Metabolic Regulators

ABSTRACTIn the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identify a loss-of-function mutation in HAD2 (PF3D7_1226300) as necessary for FSM resistance. Enzymatic characterization reveals that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we select for suppression of HAD2-mediated FSM resistance and uncover hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase (PFK9). Metabolic profiling demonstrates that FSM resistance is achieved via increased steady-state levels of MEP pathway and glycolytic intermediates and confirms reduced PFK9 function in the suppressed strains. We identify HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncover PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our study informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCEUnique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms are urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our study identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncover mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance to antimalarials.

scholarly journals From 30 million to zero malaria cases in China: lessons learned for China–Africa collaboration in malaria elimination

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jun-Hu Chen ◽  
Jun Fen ◽  
Xiao-Nong Zhou
Keyword(s):  
Public Health ◽  
Malaria Control ◽  
Malaria Elimination ◽  
Malaria Parasite ◽  
Disease Burden ◽  
Action Plan ◽  
Lessons Learned ◽  
Wide Range ◽  
Parasite Populations ◽  
First Time

AbstractMalaria was once one of the most serious public health problems in China, with more than 30 million malaria cases annually before 1949. However, the disease burden has sharply declined and the epidemic areas has shrunken after the implementation of an integrated malaria control and elimination strategy, especially since 2000. Till now, China has successfully scaled up its efforts to become malaria-free and is currently being evaluated for malaria-free certification by the WHO. In the battle against malaria, China’s efforts have spanned generations, reducing from an incidence high of 122.9/10 000 (6.97 million cases) in 1954 to 0.06/10 000 (7855 cases) in 2010. In 2017, for the first time, China reached zero indigenous case of malaria, putting the country on track to record three consecutive years of zero transmission by 2020, accoding to the National Malaria Elimination Action Plan (2010–2020). China’s efforts to eliminate malaria is impressive, and the country is dedicated to sharing its lessons learned in malaria elimination—including, but not limited to, the application of novel genetics-based approaches—with other nations through new initiatives. China will promote international relationships and establish collaborative platforms on a wide range of topics in roughly 65 countries, including 20 African nations. China’s experience in applying innovative genetics-based approaches and tools to characterize malaria parasite populations, including surveillance of markers related to drug resistance, categorization of cases as indigenous or imported, and objective identification of the likely sources of infections to inform efforts towards malaria control and elimination in Africa could offer game-changing results when applied to settings with ongoing transmission.

scholarly journals The Search for a Schistosomiasis Vaccine: Australia’s Contribution

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 872
Author(s):  
Donald P. McManus
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Sub Saharan Africa ◽  
Effective Vaccine ◽  
Neglected Tropical Disease ◽  
Vaccine Research ◽  
Health Measures ◽  
Leading Role ◽  
Invaluable Tool ◽  
Sub Saharan

Schistosomiasis, a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, results in considerable human morbidity in sub-Saharan Africa, in particular, but also parts of the Middle East, South America, and Southeast Asia. The anti-schistosome drug praziquantel is efficacious and safe against the adult parasites of all Schistosoma species infecting humans; however, it does not prevent reinfection and the development of drug resistance is a constant concern. The need to develop an effective vaccine is of great importance if the health of many in the developing world is to be improved. Indeed, vaccination, in combination with other public health measures, can provide an invaluable tool to achieve lasting control, leading to schistosomiasis elimination. Australia has played a leading role in schistosomiasis vaccine research over many years and this review presents an overview of some of the significant contributions made by Australian scientists in this important area.

scholarly journals Endemic foot and mouth disease: pastoral in-herd disease dynamics in sub-Saharan Africa

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
I. McLachlan ◽  
G. Marion ◽  
I. J. McKendrick ◽  
T. Porphyre ◽  
I. G. Handel ◽  
...  
Keyword(s):  
Disease Burden ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Sub Saharan Africa ◽  
Herd Level ◽  
Population Turnover ◽  
Foot And Mouth ◽  
Sub Saharan ◽  
Multiple Strains ◽  
Reduced Risk

AbstractFoot and mouth disease (FMD) burden disproportionally affects Africa where it is considered endemic. Smallholder livestock keepers experience significant losses due to disease, but the dynamics and mechanisms underlying persistence at the herd-level and beyond remain poorly understood. We address this knowledge gap using stochastic, compartmental modelling to explore FMD virus (FMDV) persistence, outbreak dynamics and disease burden in individual cattle herds within an endemic setting. Our analysis suggests repeated introduction of virus from outside the herd is required for long-term viral persistence, irrespective of carrier presence. Risk of new disease exposures resulting in significant secondary outbreaks is reduced by the presence of immune individuals giving rise to a period of reduced risk, the predicted duration of which suggests that multiple strains of FMDV are responsible for observed yearly herd-level outbreaks. Our analysis suggests management of population turnover could potentially reduce disease burden and deliberate infection of cattle, practiced by local livestock keepers in parts of Africa, has little effect on the duration of the reduced risk period but increases disease burden. This work suggests that FMD control should be implemented beyond individual herds but, in the interim, herd management may be used to reduced FMD impact to livestock keepers.

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