Quantitative dissection of clone-specific growth rates in cultured malaria parasites

Reilly, Heather B.; Wang, Hongjian; Steuter, John; Marx, Anastasia M.; Ferdig, Michael T.

doi:10.1016/j.ijpara.2007.05.003

Cited by 107 publications

(141 citation statements)

References 27 publications

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“…Thus, asynchrony would only impact the timing of the late peaks and would not alter the fundamental interaction between the immune system and the parasite. The constant replication rate is consistent with the in vitro evidence (24), and the density-dependent mechanism we include, which changes the percentage of parasites that infect RBCs, approximates the fold changes in parasite growth both in the malaria therapy data (47) and in experimental infections (29). Changes in the growth rate parameter did not affect the qualitative results.…”

Section: Discussionsupporting

confidence: 84%

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Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

et al. 2014

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The within-host dynamics of an infection with the malaria parasite Plasmodium falciparum are the result of a complex interplay between the host immune system and parasite. Continual variation of the P. falciparum erythrocyte membrane protein (PfEMP1) antigens displayed on the surface of infected red blood cells enables the parasite to evade the immune system and prolong infection. Despite the importance of antigenic variation in generating the dynamics of infection, our understanding of the mechanisms by which antigenic variation generates long-term chronic infections is still limited. We developed a model to examine the role of cross-reactivity in generating infection dynamics that are comparable to those of experimental infections. The hybrid computational model we developed is attuned to the biology of malaria by mixing discrete replication events, which mimics the synchrony of parasite replication and invasion, with continuous interaction with the immune system. Using simulations, we evaluated the dynamics of a single malaria infection over time. We then examined three major mechanisms by which the dynamics of a malaria infection can be structured: cross-reactivity of the immune response to PfEMP1, differences in parasite clearance rates, and heterogeneity in the rate at which antigens switch. The results of our simulations demonstrate that cross-reactive immune responses play a primary role in generating the dynamics observed in experimentally untreated infections and in lengthening the period of infection. Importantly, we also find that it is the primary response to the initially expressed PfEMP1, or small subset thereof, that structures the cascading cross-immune dynamics and allows for elongation of the infection.

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Section: Discussionsupporting

confidence: 84%

“…We assume that parasites that survive the 48-h period of replication without being cleared by the immune system produce 18 new merozoites (24,28,29). We further assume that a fraction of these new merozoites infects RBCs.…”

Section: Methodsmentioning

confidence: 99%

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

et al. 2014

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“…Some authors found that high baseline parasitemia density may be a predictor of CQ resistance in patients presenting falciparum malaria (27,28). It is known that laboratory strains of P. falciparum (29) and P. vivax (30) have a marked variability in growth rates, with CQ-resistant isolates growing faster than CQ-susceptible isolates.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium vivax Chloroquine Resistance and Anemia in the Western Brazilian Amazon

Marques

Costa

Filho

et al. 2014

Antimicrob Agents Chemother

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Data on chloroquine (CQ)-resistant Plasmodium vivax in LatinAmerica is limited, even with the current research efforts to sustain an efficient malaria control program in all these countries where P. vivax is endemic and where malaria still is a major public health issue. This study estimated in vivo CQ resistance in patients with uncomplicated P. vivax malaria, with use of CQ and primaquine simultaneously, in the Brazilian Amazon. Of a total of 135 enrolled subjects who accomplished the 28-day follow-up, parasitological failure was observed in 7 (5.2%) patients, in whom plasma CQ and desethylchloroquine (DCQ) concentrations were above 100 ng/dl. Univariate analysis showed that previous exposure to malaria and a higher initial mean parasitemia were associated with resistance but not with age or gender. In the multivariate analysis, only high initial parasitemia remained significant. Hemoglobin levels were similar at the beginning of the follow-up and were not associated with parasitemia. However, at day 3 and day 7, hemoglobin levels were significantly lower in patients presenting CQ resistance. The P. vivax dhfr (pvdhfr), pvmrp1, pvmdr1, and pvdhps gene mutations were not related to resistance in this small sample. P. vivax CQ resistance is already a problem in the Brazilian Amazon, which could be to some extent associated with the simultaneous report of anemia triggered by this parasite, a common complication of the disease in most of the areas of endemicity.

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“…Two strains of P falciparum were used in these experiments: the CQ-sensitive FCMSU1/Sudan strain was donated [12] and the CQresistant Indochina (W2) strain was provided by Dr. W.K. Milhous.…”

Section: Methodsmentioning

confidence: 99%

“…Milhous. Both parasite strains were cultured in our lab for over two years using the candle jar method [12]. For a given experiment, 4-day-old Petri dish cultures with 5-10% parasitemia were diluted with medium containing sufficient non-parasitized human type A erythrocytes to obtain a culture with a final hematocrit of 1.5% and parasitemia of 0.5-1.0%.…”

Section: Methodsmentioning

confidence: 99%

Antimalarial Activity of Various Bisbenzylisoquinoline and AporphineBenzylisoquinoline Alkaloids and their Structure-Activity Relationships against Chloroquine – Sensitive and Resistant Plasmodium falciparum Malaria in vitro

Ye¹,

Dyke

2015

Malaria Contr Elimination

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The antimalarial activity of some bisbenzylisoquinoline (BBIQ) alkaloids were studied using in vitro culture of both chloroquine (CQ)-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The combination of chloroquine and tetrandrine gave a 44 fold potentiation of malarial killing. Fangchinoline, hernandezine, pycnamine, berbamine and isotetrandrine had similar antimalarial activity as tetrandrine against the sensitive strain of P. falciparum malaria. Hernandezine, isotetrandrine, berbamine, fangchinoline and methoxyadiantifoline had similar antimalarial activity as tetrandrine against a strain of chloroquine-resistant falciparum malaria. Based on structure/ activity analysis, we concluded that the stereochemistry of C-1ʹ (S ring) of the BBIQ structure played an important role in selective action against resistant malaria. The stereochemistry of C-1 (left ring) and a substituent of C-12 appeared to have little influence on the selectivity. The point of attachment of the ether bridges to the rings also exerts an important influence on selective antimalarial activity. Tetrandrine (TT) penetrates both the erythrocyte and parasite membranes and inhibits the synthesis and activity of the (MDR) pump and likely the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) since it inhibits the calcium channel. These observations likely account for the fact TT potentiates the activity of chloroquine more than 40 fold against chloroquine resistant falciparum malaria.

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Quantitative dissection of clone-specific growth rates in cultured malaria parasites

Cited by 107 publications

References 27 publications

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

Cross-Reactive Immune Responses as Primary Drivers of Malaria Chronicity

Plasmodium vivax Chloroquine Resistance and Anemia in the Western Brazilian Amazon

Antimalarial Activity of Various Bisbenzylisoquinoline and AporphineBenzylisoquinoline Alkaloids and their Structure-Activity Relationships against Chloroquine – Sensitive and Resistant Plasmodium falciparum Malaria in vitro

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