Severe Malaria: Metabolic Complications

Planche, Tim; Krishna, Sanjeev

doi:10.2174/156652406776055177

Cited by 42 publications

(33 citation statements)

References 99 publications

(146 reference statements)

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“…Infection begins when Anopheles mosquitoes deliver sporozoite forms that invade hepatocytes and replicate as liverstage parasites, before emerging into the blood stream and infecting red blood cells. The asexual blood-stage infection causes clinical disease characterized by cyclical fevers and shaking chills, which can lead to complications such as severe anemia or cerebral malaria [3,4]. Red blood cells can also harbor sexual-stage gametocytes that can be transmitted to mosquitoes, where they undergo genetic recombination and complete the lifecycle of the parasite.…”

Section: Malaria and Drug Resistancementioning

confidence: 99%

Transporters involved in resistance to antimalarial drugs

Valderramos

Fidock

2006

Trends in Pharmacological Sciences

163

150

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The ability to treat and control Plasmodium falciparum infection through chemotherapy has been compromised by the advent and spread of resistance to antimalarial drugs. Research in this area has identified the P. falciparum chloroquine resistance transporter (PfCRT) and the multidrug resistance-1 (PfMDR1) transporter as key determinants of decreased in vitro susceptibility to several principal antimalarial drugs. Transfection-based in vitro studies are consistent with clinical findings of an association between mutations in the pfcrt gene and failure of chloroquine treatment, and between amplification of the pfmdr1 gene and failure of mefloquine treatment. Many countries are now switching to arte-misinin-based combination therapies. These incorporate partner drugs of which some have an in vitro efficacy that can be modulated by changes in pfcrt or pfmdr1. Here, we summarize investigations of these and other recently identified P. falciparum transporters in the context of antimalarial mode of action and mechanisms of resistance. Malaria and drug resistanceThe spread of drug resistant strains of the malaria parasite Plasmodium falciparum has led to a significant resurgence of malarial morbidity and mortality, and a growing crisis in global public health [1]. P. falciparum causes an estimated 500 million clinical infections and at least one million deaths annually, primarily in sub-Saharan Africa [1,2]. Infection begins when Anopheles mosquitoes deliver sporozoite forms that invade hepatocytes and replicate as liverstage parasites, before emerging into the blood stream and infecting red blood cells. The asexual blood-stage infection causes clinical disease characterized by cyclical fevers and shaking chills, which can lead to complications such as severe anemia or cerebral malaria [3,4]. Red blood cells can also harbor sexual-stage gametocytes that can be transmitted to mosquitoes, where they undergo genetic recombination and complete the lifecycle of the parasite.For decades, the treatment of malaria depended on chloroquine -an extensively used 4-aminoquinoline characterized by its rapid efficacy, low toxicity, availability and affordability [5]. The eventual appearance of chloroquine resistance in Southeast Asia and South America sparked the global dissemination of resistance [6]. The first-line treatment for chloroquineresistant (CQR) malaria -sulfadoxine-pyrimethamine -rapidly met with resistance and is also becoming increasingly ineffective [7]. Failure of P. falciparum clinical treatment resulting from confirmed in vivo parasite resistance has now been documented for all current antimalarial drugs apart from the artemisinins, placing artemisinin-based combination therapy at the forefront of current malaria control programs [8,9].Here, we review recent studies into the P. falciparum chloroquine resistance (PfCRT) and multidrug resistance-1 (PfMDR1) transporters that are now known to be key contributors to P. falciparum antimalarial drug resistance. We also briefly discuss the Ca 2+ transporter PfATP6, ...

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Section: Malaria and Drug Resistancementioning

confidence: 99%

Transporters involved in resistance to antimalarial drugs

Valderramos

Fidock

2006

Trends in Pharmacological Sciences

163

150

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“…Tissue factor activation on endothelial cells has also been demonstrated on incubating the endothelial cells with parasitised RBC (Pernod et al 1992;Clemens et al 1994). Parasitised red cells also block deep visceral capillaries by its attachment with endothelium and leads to lactic acidosis in severe falciparum malaria (Jarvis et al 2006;Planche and Krishna 2006) It is well known that coagulation system, being a cascade of enzymatically driven activity, does not function very well in the presence of acidosis. Table 1 Biochemical changes and changes in cytokine production in falciparum malarias (Clark et al 2006) Cytokine production in falciparum malarias Change(s) Cytokine storm deranging the coagulation system Several workers have studied the pattern of cytokine imbalance as a consequence of severe falciparum malaria (Day et al 1999;Chaiyaroj et al 2004).…”

Section: Activation Of Coagulation By Parasitised Red Cellsmentioning

confidence: 99%

Blood coagulation in falciparum malaria—a review

Ghosh

Shetty

2007

Parasitol Res

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Falciparum malaria infection influences blood coagulation by various interacting pathobiological mechanisms, the most important being the overwhelming response of the host to sepsis resulting in a cytokine storm. In addition, the parasite infects the red cells leading to changes in the red cell phospholipid composition which supports blood coagulation. Red cells infected with Plasmodium falciparum also adhere to deeper tissue capillary endothelium leading to profound damage to endothelial cells leading to further activation. This results in widespread consumption of platelets and activation of blood coagulation which at times culminates in a clinically and pathologically detectable disseminated intravascular coagulation (DIC). Monocyte-macrophage system also gets activated in this infection compounding the hypercoagulable state. Heavy parasitaemia leading to occlusion of hepatic microcirculation leads to abnormalities in synthesis and secretion of coagulation factors and their inhibitors. Drugs used in the treatment for falciparum malaria can cause thrombocytopaenia, bone marrow suppression and haemolytic anaemia, all of which can interfere indirectly with blood coagulation. Microparticle formation from platelets, red cells and macrophages also causes widespread activation of blood coagulation, and this recently observed mechanism is the focus of intense research in many other inflammatory and neoplastic conditions where there is activation of blood coagulation system. Thus, in severe falciparum malaria, there is activation of blood coagulation system along with thrombocytopaenia, even before widespread DIC and coagulation failure occur.

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“…iRBCs can either bind to endothelial cells 7 , form rosettes with uninfected RBCs 8, 9 , or cluster amongst themselves via platelet interactions 10 . Sequestered iRBCs occlude microvasculature 11, 12 , induce the release of damaging inflammatory mediators 13 , and cause disruptions to host metabolism 14 . Cerebral malaria, a lethal manifestation of P. falciparum , occurs when iRBCs sequester in the microvasculature in the brain 15 .…”

Section: Introductionmentioning

confidence: 99%

Single molecule and multiple bond characterization of catch bond associated cytoadhesion in malaria

Lim

Thingna

Cao

et al. 2017

Sci Rep

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The adhesion of malaria infected red blood cells (iRBCs) to host endothelial receptors in the microvasculature, or cytoadhesion, is associated with severe disease pathology such as multiple organ failure and cerebral malaria. Malaria iRBCs have been shown to bind to several receptors, of which intercellular adhesion molecule 1 (ICAM-1) upregulation in brain microvasculature is the only one correlated to cerebral malaria. We utilize a biophysical approach to study the interactions between iRBCs and ICAM-1. At the single molecule level, force spectroscopy experiments reveal that ICAM-1 forms catch bond interactions with Plasmodium falciparum parasite iRBCs. Flow experiments are subsequently conducted to understand multiple bond behavior. Using a robust model that smoothly transitions between our single and multiple bond results, we conclusively demonstrate that the catch bond behavior persists even under flow conditions. The parameters extracted from these experimental results revealed that the rate of association of iRBC-ICAM-1 bonds are ten times lower than iRBC-CD36 (cluster of differentiation 36), a receptor that shows no upregulation in the brains of cerebral malaria patients. Yet, the dissociation rates are nearly the same for both iRBC-receptor interactions. Thus, our results suggest that ICAM-1 may not be the sole mediator responsible for cytoadhesion in the brain.

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Severe Malaria: Metabolic Complications

Cited by 42 publications

References 99 publications

Transporters involved in resistance to antimalarial drugs

Transporters involved in resistance to antimalarial drugs

Blood coagulation in falciparum malaria—a review

Single molecule and multiple bond characterization of catch bond associated cytoadhesion in malaria

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