Sporozoite Route of Infection Influences In Vitro<i>var</i>Gene Transcription of<i>Plasmodium falciparum</i>Parasites From Controlled Human Infections

Dimonte, Sandra; Bruske, Ellen; Hass, Johanna; Supan, Christian; Salazar, Carmen L. Ospina; Held, Jana; Tschan, Serena; Esen, Meral; Flötenmeyer, Matthias; Koch, Iris; Berger, Jürgen; Bachmann, Anna; Sim, B. Kim Lee; Hoffman, Stephen L.; Kremsner, Peter G.; Mordmüller, Benjamin; Frank, Matthias

doi:10.1093/infdis/jiw225

Cited by 19 publications

(35 citation statements)

References 41 publications

(66 reference statements)

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“…In 2012, our group established a model using direct venous inoculation of P. falciparum sporozoites in malaria‐naïve volunteers, which is highly reproducible showing an infection rate of 100% . This was seen in many more trials with all unprotected naïve volunteers having very similar parasitaemia curves . Of note, the same infection model has been used to assess causal prophylaxis at two clinical trial sites and showed that it is adequately powered to detect partial efficacy in small group sizes .…”

Section: Discussionmentioning

confidence: 98%

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Metzger

Theurer

Pfleiderer

et al. 2020

Tropical Med Int Health

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Objective Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection. Methods A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT‐qPCR was performed in parallel. Results All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia. Conclusion Ivermectin – at the dose used – has no clinically relevant activity against the pre‐erythrocytic stages of P. falciparum.

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Section: Discussionmentioning

confidence: 98%

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Metzger

Theurer

Pfleiderer

et al. 2020

Tropical Med Int Health

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“…Therefore, volunteers are infected with exactly the same material and, when given by DVI, using a tightly controlled dose, an approach that cannot be reproduced using mosquitoes. Consequently, expression patterns of immunologically variant antigens, i.e., var genes in malaria-naive volunteers, are conserved, 25 , 26 a prerequisite to understand naturally acquired immunity.…”

Section: Discussionmentioning

confidence: 99%

Impact of Sickle Cell Trait and Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human Malaria Infection in Adults in Gabon

Lell

Mordmüller

Dejon-Agobé

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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Abstract.Controlled human malaria infection (CHMI) by direct venous inoculation (DVI) with 3,200 cryopreserved Plasmodium falciparum sporozoites (PfSPZ) consistently leads to parasitemia and malaria symptoms in malaria-naive adults. We used CHMI by DVI to investigate infection rates, parasite kinetics, and malaria symptoms in lifelong malaria–exposed (semi-immune) Gabonese adults with and without sickle cell trait. Eleven semi-immune Gabonese with normal hemoglobin (IA), nine with sickle cell trait (IS), and five nonimmune European controls with normal hemoglobin (NI) received 3,200 PfSPZ by DVI and were followed 28 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction (qPCR) and for malaria symptoms. End points were time to parasitemia and parasitemia plus symptoms. PfSPZ Challenge was well tolerated and safe. Five of the five (100%) NI, 7/11 (64%) IA, and 5/9 (56%) IS volunteers developed parasitemia by TBS, and 5/5 (100%) NI, 9/11 (82%) IA, and 7/9 (78%) IS by qPCR, respectively. The time to parasitemia by TBS was longer in IA (geometric mean 16.9 days) and IS (19.1 days) than in NA (12.6 days) volunteers (P = 0.016, 0.021, respectively). Five of the five, 6/9, and 1/7 volunteers with parasitemia developed symptoms (P = 0.003, NI versus IS). Naturally adaptive immunity (NAI) to malaria significantly prolonged the time to parasitemia. Sickle cell trait seemed to prolong it further. NAI plus sickle cell trait, but not NAI alone, significantly reduced symptom rate. Twenty percent (4/20) semi-immunes demonstrated sterile protective immunity. Standardized CHMI with PfSPZ Challenge is a powerful tool for dissecting the impact of innate and naturally acquired adaptive immunity on malaria.

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“…NF54 passage through mosquito and human host resulted in a complete shift in var gene transcription compared to the premosquito [59] culture. Subsequent in vitro tissue culture growth showed that cultures from intradermally and intravenously infected individuals transcribed the same var genes but that the transcription signals were higher in parasites recovered after intradermal sporozoite inoculation [32]. Parasites from intradermal sporozoites infections showed higher surface signals after incubation with the MOA serum than parasites from intravenous infections.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time this is associated with a lower switching propensity, suggesting that epigenetic modifications can influence the transcription activity and switching propensity of a recombinant var promoter. In a recent investigation of NF54 parasites recovered from controlled human infections [58], we have shown that longer in-host replication results in parasite populations with strong var gene transcription signals and low switching propensities [32]. …”

Section: Discussionmentioning

confidence: 99%

“…Epigenetic memory appears to “mark” the active var locus [23,26] to ensure its continued expression in the next generation of offspring and it has been shown that individual active promoters are stably transcribed for prolonged periods of time [27]. in vitro switching investigations with long term laboratory strains and with parasites obtained from controlled human infections [28–32], provide evidence that var gene switching is highly structured and suggest a repeatable hierarchy of var gene activation. These observations raise the question of how such a stably inherited transcription pattern is compatible with antigenic variation during natural chronic infections in endemic areas.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Variant Surface Antigen Expression in Plasmodium falciparum Parasites from a Semi-Immune Individual Is Not Correlated with Var Gene Transcription

et al. 2016

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Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is considered to be the main variant surface antigen (VSA) of Plasmodium falciparum and is mainly localized on electron-dense knobs in the membrane of the infected erythrocyte. Switches in PfEMP1 expression provide the basis for antigenic variation and are thought to be critical for parasite persistence during chronic infections. Recently, strain transcending anti-PfEMP1 immunity has been shown to develop early in life, challenging the role of PfEMP1 in antigenic variation during chronic infections. In this work we investigate how P. falciparum achieves persistence during a chronic asymptomatic infection. The infected individual (MOA) was parasitemic for 42 days and multilocus var gene genotyping showed persistence of the same parasite population throughout the infection. Parasites from the beginning of the infection were adapted to tissue culture and cloned by limiting dilution. Flow cytometry using convalescent serum detected a variable surface recognition signal on isogenic clonal parasites. Quantitative real-time PCR with a field isolate specific var gene primer set showed that the surface recognition signal was not correlated with transcription of individual var genes. Strain transcending anti-PfEMP1 immunity of the convalescent serum was demonstrated with CD36 selected and PfEMP1 knock-down NF54 clones. In contrast, knock-down of PfEMP1 did not have an effect on the antibody recognition signal in MOA clones. Trypsinisation of the membrane surface proteins abolished the surface recognition signal and immune electron microscopy revealed that antibodies from the convalescent serum bound to membrane areas without knobs and with knobs. Together the data indicate that PfEMP1 is not the main variable surface antigen during a chronic infection and suggest a role for trypsin sensitive non-PfEMP1 VSAs for parasite persistence in chronic infections.

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Sporozoite Route of Infection Influences In VitrovarGene Transcription ofPlasmodium falciparumParasites From Controlled Human Infections

Abstract: The duration of intrahost replication influences in vitro var gene transcript patterns. Differences between premosquito and postpatient cultures decrease with prolonged in vitro growth.

Cited by 19 publications

References 41 publications

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial

Impact of Sickle Cell Trait and Naturally Acquired Immunity on Uncomplicated Malaria after Controlled Human Malaria Infection in Adults in Gabon

In Vitro Variant Surface Antigen Expression in Plasmodium falciparum Parasites from a Semi-Immune Individual Is Not Correlated with Var Gene Transcription

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