1. Microbiology and Infectious Disease
Download icon

Malaria: On a mission to block transmission

  1. Amanda Ross  Is a corresponding author
  2. Nicolas MB Brancucci
  1. Swiss Tropical and Public Health Institute, Switzerland
  2. University of Basel, Switzerland
Insight
  • Cited 1
  • Views 2,219
  • Annotations
Cite this article as: eLife 2018;7:e35246 doi: 10.7554/eLife.35246

Abstract

The controlled infection of volunteers with Plasmodium falciparum parasites could provide a platform to evaluate new drugs and vaccines aimed at blocking malaria transmission.

Main text

Life inside a human host is fraught with danger. Plasmodium falciparum malaria parasites need to be highly adapted to compete for resources and to take their chances with the immune system. The same degree of specialization is needed to survive inside the mosquito, and for the transitions from human to mosquito and vice versa. These seemingly incompatible needs are met by a life cycle that involves morphing into a series of different forms.

Under the microscope, a blood sample may reveal different stages of the parasite: asexual parasites that replicate and prolong the infection, and sexual stages called gametocytes, the form that transmits the infection from human to mosquito. Both male and female gametocytes arise when a small proportion of asexual parasites stop replication and commit to sexual development instead. After maturation they are either taken up by a feeding mosquito or die. Sex and transmission are inextricably linked. Fertilization occurs inside the mosquito gut within an hour of feeding and leads to several developmental phases inside the insect vector, after which parasites are ready to infect a new human host (Sinden, 2017).

Most licensed antimalarial drugs target the asexual forms of the parasite. These stages are the most abundant and cause the symptoms of malaria (Sinden, 2017; Nilsson et al., 2015). As the burden of disease has declined in many regions and the focus is shifting towards malaria elimination, the searchlight beam now falls onto other stages. On paper, gametocytes are a good target to break the circle of transmission: they are the only form capable of infecting mosquitoes and their low number creates a population bottleneck.

However, efforts to introduce new drugs and vaccines that target gametocytes and prevent malaria transmission face an obstacle: there is no method to directly evaluate their success in humans. Clinical studies in malaria patients can demonstrate the effect of drugs on asexual parasites, but often fail to capture the dynamics of gametocytes for simple reasons. Gametocytes generally occur at very low densities and are often missed by standard detection methods. They sequester away from the blood stream for eight to twelve days as they mature, and often are not seen at the time of illness. Consequently, the evaluation of drugs is mostly limited to unnatural conditions, such as measuring gametocyte densities in cell cultures or artificially feeding blood infected with gametocytes to mosquitoes.

Now, in eLife, Robert Sauerwein, Teun Bousema and colleagues – including Isaie Reuling as first author – report a promising method to fill this void (Reuling et al., 2018). The researchers – who are based at the Radboud University Medical Center and other universities and non-profit organizations in the UK, United States, Australia and the Netherlands – drew on recent scientific developments in sensitive molecular diagnostic methods, the stage-specificity of drugs and the resurgence of interest in human challenge studies (Farid et al., 2017; Stanisic et al., 2018; Stone et al., 2017).

Reuling et al. deliberately infected volunteers with P. falciparum using Anopheles mosquitoes. The ensuing asexual parasite densities were controlled and eventually cleared using different drugs while allowing the gametocytes to continue development under safe conditions. All of the volunteers yielded circulating gametocytes.

A crucial question is how well this method of generating gametocytes in humans would work to evaluate a compound that blocks transmission. Effects on gametocyte densities can be shown (Collins et al., 2018). However, such densities are only loosely related to transmission success (Churcher et al., 2013). The most relevant measure would be whether or not feeding mosquitoes become infected. Reuling et al. observed that the low gametocyte numbers in the volunteers only sporadically infected mosquitoes, and are aware that this renders conclusions about transmission-blocking activity impossible.

Changing certain elements of the study setup, for example using different drugs, treatment doses, P. falciparum laboratory strains or mosquito species, may overcome this issue. Another possibility could be to enhance gametocyte production by inducing sexual commitment. However, we are only beginning to understand the triggers for this process (Bechtsi and Waters, 2017). Recently, a human lipid was shown to inhibit sexual commitment (Brancucci et al., 2017). Interfering with the underlying regulatory pathway could be exploited in the future. But regardless of how these problems are tackled, questions of how well the system translates into real life settings would need to be addressed carefully.

A side-effect of piloting the method of controlled human infection is the insight into the secret lives of gametocytes. Previously, the most detailed studies of gametocyte dynamics had been made when deliberate infections were used to treat neurosyphilis patients at a time before antibiotics were available (Snounou and Pérignon, 2013). By using highly sensitive and sex-specific detection methods, Reuling et al. add to the pool of knowledge and provide evidence that mature male and female gametocytes first appear in the blood at different times, and that female gametocytes circulate in the blood for longer. The early appearance of mature gametocytes in the peripheral blood of the volunteers further suggests that a fraction of the first wave of parasites entering the blood stream can already be sexually committed.

A system to evaluate potential transmission-blocking strategies in vivo is hugely appealing. In future, an optimized setup that can achieve a higher proportion of infected mosquitoes may help to discover new ways to prevent malaria transmission. The work of Reuling et al. has opened a door.

Red blood cells infected with Plasmodium falciparum parasites.

Malaria parasites have a complex life cycle and different forms of the parasites can be found in the blood. This scanning electron micrograph shows red blood cells infected with the parasite: an asexual stage on the left and a mature gametocyte on the right. Only the gametocytes can infect mosquitoes.

© Brand, 2018. Image courtesy of Françoise Brand, Swiss Tropical and Public Health Institute and University of Basel. Published under a CC BY 4.0 license.

References

Article and author information

Author details

  1. Amanda Ross

    Amanda Ross is in the Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland and the University of Basel, Basel, Switzerland.

    For correspondence
    amanda.ross@swisstph.ch
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6027-5645
  2. Nicolas MB Brancucci

    Nicolas MB Brancucci is in the Department of Molecular Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland and the University of Basel, Basel, Switzerland.

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0655-3266

Acknowledgements

The authors thank Eilidh Carrington, Natalie Hofmann, Melissa Penny, Matthias Rottmann, Tom Smith and Till Voss for helpful discussions.

Publication history

  1. Version of Record published: February 27, 2018 (version 1)

Copyright

© 2018, Ross et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,219
    Page views
  • 421
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Gemma Moncunill et al.
    Research Article

    Background:

    In a phase 3 trial in African infants and children, the RTS,S/AS01 vaccine (GSK) showed moderate efficacy against clinical malaria. We sought to further understand RTS,S/AS01-induced immune responses associated with vaccine protection.

    Methods:

    Applying the blood transcriptional module (BTM) framework, we characterized the transcriptomic response to RTS,S/AS01 vaccination in antigen-stimulated (and vehicle control) peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (1-month post-third dose). Using a matched case–control study design, we evaluated which of these ‘RTS,S/AS01 signature BTMs’ associated with malaria case status in RTS,S/AS01 vaccinees. Antigen-specific T-cell responses were analyzed by flow cytometry. We also performed a cross-study correlates analysis where we assessed the generalizability of our findings across three controlled human malaria infection studies of healthy, malaria-naive adult RTS,S/AS01 recipients.

    Results:

    RTS,S/AS01 vaccination was associated with downregulation of B-cell and monocyte-related BTMs and upregulation of T-cell-related BTMs, as well as higher month 3 (vs. baseline) circumsporozoite protein-specific CD4+ T-cell responses. There were few RTS,S/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of BTMs associated with dendritic cells and with monocytes (among others) correlated with malaria risk. The baseline dendritic cell- and monocyte-related BTM correlations with malaria risk appeared to generalize to healthy, malaria-naive adults.

    Conclusions:

    A prevaccination transcriptomic signature associates with malaria in RTS,S/AS01-vaccinated African children, and elements of this signature may be broadly generalizable. The consistent presence of monocyte-related modules suggests that certain monocyte subsets may inhibit protective RTS,S/AS01-induced responses.

    Funding:

    Funding was obtained from the NIH-NIAID (R01AI095789), NIH-NIAID (U19AI128914), PATH Malaria Vaccine Initiative (MVI), and Ministerio de Economía y Competitividad (Instituto de Salud Carlos III, PI11/00423 and PI14/01422). The RNA-seq project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under grant number U19AI110818 to the Broad Institute. This study was also supported by the Vaccine Statistical Support (Bill and Melinda Gates Foundation award INV-008576/OPP1154739 to R.G.). C.D. was the recipient of a Ramon y Cajal Contract from the Ministerio de Economía y Competitividad (RYC-2008-02631). G.M. was the recipient of a Sara Borrell–ISCIII fellowship (CD010/00156) and work was performed with the support of Department of Health, Catalan Government grant (SLT006/17/00109). This research is part of the ISGlobal’s Program on the Molecular Mechanisms of Malaria which is partially supported by the Fundación Ramón Areces and we acknowledge support from the Spanish Ministry of Science and Innovation through the ‘Centro de Excelencia Severo Ochoa 2019–2023’ Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.

    1. Cell Biology
    2. Microbiology and Infectious Disease
    Jeffrey Y Lee et al.
    Research Article

    Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisation (smFISH) to quantify positive sense RNA genomes with 95% detection efficiency, while simultaneously visualising negative sense genomes, subgenomic RNAs, and viral proteins. Our absolute quantification of viral RNAs and replication factories revealed that SARS-CoV-2 genomic RNA is long-lived after entry, suggesting that it avoids degradation by cellular nucleases. Moreover, we observed that SARS-CoV-2 replication is highly variable between cells, with only a small cell population displaying high burden of viral RNA. Unexpectedly, the B.1.1.7 variant, first identified in the UK, exhibits significantly slower replication kinetics than the Victoria strain, suggesting a novel mechanism contributing to its higher transmissibility with important clinical implications.