Pre-erythrocytic Stage of Plasmodium Falciparum

Shortt, H. E.; Fairley, N. Hamilton; Covell, G.; Shute, P. G.; Garnhám, P. C. C.

doi:10.1136/bmj.2.4635.1006

Cited by 52 publications

(40 citation statements)

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“…In our hands this method detects two parasites/ml of blood, consistent with previous reports 29 and roughly equivalent to the sensitivity of in vitro culture. 30 If just one parasite injected by a mosquito generates 30,000 in the liver, 31,32 then the initial parasitemia should be ϳ6/ml, a level readily detectable by our PCR and culture methods.…”

Section: Methodsmentioning

confidence: 99%

“…Follow-up visits were scheduled daily (days 5-21), every other day (days [22][23][24][25][26][27][28][29][30][31][32][33][34][35], then weekly until 12 weeks after challenge. Volunteers returned one year after challenge for final evaluation and to have the bracelets removed.…”

Section: Methodsmentioning

confidence: 99%

“…Although 6.5 days was chosen as the theoretical start point for erythrocytic infection, the experimental results are not substantially different if the AUC is taken from day 5.5 (the mean Ϯ SD AUC 5.5-11.5 is 0.85 Ϯ 0.61 g ·day/ml), the earliest appearance reported for any strain of P. falciparum. 32 Indeed, for some of our low-dose subjects, AUC values calculated from day 6.5 may overestimate the amount of drug present during earliest parasitemia: two placebo recipients had no detectable circulating parasites until 10 or 16 days after challenge (Figure 1).…”

Section: Study Populationmentioning

confidence: 99%

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Prophylactic activity of atovaquone against Plasmodium falciparum in humans.

Shapiro

Ranasinha²,

Kumar

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The prophylactic antimalarial activity of atovaquone was determined in a randomized, double-blind, placebocontrolled study of healthy volunteers who were challenged by the bite of Plasmodium falciparum-infected Anopheles stephensi. Subjects were randomly assigned to one of three groups: six received seven daily doses of 750 mg of atovaquone, starting the day before challenge; six received a single dose of 250 mg of atovaquone the day before challenge; and four received placebo. Polymerase chain reaction-and culture-confirmed parasitemia developed in all four placebo recipients, but in none of the drug recipients, indicating that either of the atovaquone regimens provides effective prophylaxis (P ϭ 0.005). However, in low-dose recipients, the drug levels by day 6.5 were profoundly subtherapeutic, indicating that parasites were eliminated prior to the establishment of erythrocytic infection. Atovaquone thus protects non-immune subjects against mosquito-transmitted falciparum malaria, and has causal prophylactic activity.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

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Prophylactic activity of atovaquone against Plasmodium falciparum in humans.

Shapiro

Ranasinha²,

Kumar

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The reported sizes of late P. falciparum LSs obtained from in vitro culture range from only 15 to 40 μm in diameter (6,7,39,40), whereas we visualized LS sizes up to 80 μm in diameter, which, based on previous volume calculations (29), contain between 40,000 and 60,000 merozoites. A small number of studies on P. falciparum LS development in humans have been undertaken (41,42), and the size of 6 day LS ranged from 55 to 60 μm. A more complete microscopic study of mature P. falciparum LS in the chimpanzee, which is susceptible to both P. falciparum preerythrocytic and blood-stage infections, has also been carried out, showing late LS measured from 60 to 100 μm in diameter (43).…”

Section: Frg Huhep and Frg Nod Huhep Micementioning

confidence: 99%

Complete Plasmodium falciparum liver-stage development in liver-chimeric mice

et al. 2012

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Plasmodium falciparum, which causes the most lethal form of human malaria, replicates in the host liver during the initial stage of infection. However, in vivo malaria liver-stage (LS) studies in humans are virtually impossible, and in vitro models of LS development do not reconstitute relevant parasite growth conditions. To overcome these obstacles, we have adopted a robust mouse model for the study of P. falciparum LS in vivo: the immunocompromised and fumarylacetoacetate hydrolase-deficient mouse (Fah -/-, Rag2 -/-, Il2rg -/-, termed the FRG mouse) engrafted with human hepatocytes (FRG huHep). FRG huHep mice supported vigorous, quantifiable P. falciparum LS development that culminated in complete maturation of LS at approximately 7 days after infection, providing a relevant model for LS development in humans. The infections allowed observations of previously unknown expression of proteins in LS, including P. falciparum translocon of exported proteins 150 (PTEX150) and exported protein-2 (EXP-2), components of a known parasite protein export machinery. LS schizonts exhibited exoerythrocytic merozoite formation and merosome release. Furthermore, FRG mice backcrossed to the NOD background and repopulated with huHeps and human red blood cells supported reproducible transition from LS infection to blood-stage infection. Thus, these mice constitute reliable models to study human LS directly in vivo and demonstrate utility for studies of LS-to-blood-stage transition of a human malaria parasite. IntroductionPlasmodium falciparum is the most deadly of the human malaria parasites. The disease continues to be a global health crisis and causes more than 250 million new clinical cases annually, resulting in over 800,000 deaths, mostly of children in sub-Saharan Africa (1). Female anopheline mosquitoes introduce infectious sporozoites into the host dermis when taking a blood meal. Sporozoites exit the bite site by migration, enter a blood vessel, and are carried to the liver (2). Here, each sporozoite traverses numerous hepatocytes before it invades a final hepatocyte with the formation of a parasitophorous vacuole (PV) (3). Ensconced in the PV, the parasite undergoes liver-stage (LS, also called exoerythrocytic form [EEF]) development, culminating in the formation and release of tens of thousands of first generation merozoites (4). This preerythrocytic phase of the parasite life cycle is asymptomatic, and all clinical pathologies are caused by the ensuing asexual erythrocytic stage of infection. The erythrocytic stages are routinely studied in vitro, made possible by the development of a continuous culture system that allows asexual parasite replication in human rbc (hurbc) (5). However, studying the biology and pathophysiology of P. falciparum in vivo is difficult and is hampered by the lack of adequate animal models. Sporogonic stages are generated by feeding female Anopheles mosquitoes on in vitro gametocyte cultures, allowing progression of the parasite life cycle in the mosquito and subsequent sporozoite accumulation...

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“…Exoerythrocytic schizogony of Plasmodium elongatum in tissue cells was described by Raffaele (1934) [7]. Shortt and Garnham (1948) reported the pre-erythrocytic cycle of Plasmodium cyanomolgi [8] and P. vivax; whereas, that of P. falciparum was discovered by Shortt et al (1951) [9].…”

Section: Historical Perspectivementioning

confidence: 99%

Malaria - The Formidable Enemy of Humanity

Pawar

Pal

2015

ILNS

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Malaria, a disease caused by protozoan parasite of the genus Plasmodium, is an ancient enemy of the human race. Despite enormous efforts to control, it is still a main cause of morbidity and mortality in many endemic countries of the world, particularly Africa, South of Sahara. Malaria seems to be unstoppable due to lack of an effective vaccine, acquisition of drug-resistance by malaria parasite, and insecticide resistance by Anopheles mosquitoes. In this scenario, along with search for novel preventive approaches, adequate health facilities, health literacy and awareness among people are required to control and eliminate this formidable disease from society.

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Pre-erythrocytic Stage of Plasmodium Falciparum

Cited by 52 publications

References 1 publication

Prophylactic activity of atovaquone against Plasmodium falciparum in humans.

Prophylactic activity of atovaquone against Plasmodium falciparum in humans.

Complete Plasmodium falciparum liver-stage development in liver-chimeric mice

Malaria - The Formidable Enemy of Humanity

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