Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment
- KEMRI-Wellcome Trust Research Programme, Kenya
- University of Glasgow, United Kingdom
- Radboud University Nijmegen Medical Centre, Netherlands
Abstract
The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor ap2-g, is known to be influenced by host factors but a comprehensive model remains uncertain. Here we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission. We examine markers of host immunity and metabolism, and markers of parasite growth and transmission investment. We find that inflammatory responses associated with reduced plasma lysophosphatidylcholine levels are associated with markers of increased investment in parasite sexual reproduction (i.e., transmission investment) and reduced growth (i.e., asexual replication). This association becomes stronger with falling transmission and suggests that parasites can rapidly respond to the within-host environment, which in turn is subject to changing transmission.
Data availability
Raw data and script for all the analyses in this manuscript are available at https://doi.org/10.7910/DVN/BXXVRY. mzML mass spectrometry files are available at MetaboLights at https://www.ebi.ac.uk/metabolights/editor/study/MTBLS5130
Article and author information
Author details
João Luiz Silva-Filho
Funding
Wellcome Trust (110166)
- Fiona Achcar
- Lauriane Sollelis
- João Luiz Silva-Filho
- Matthias Marti
Wellcome Trust (104111)
- Fiona Achcar
- Lauriane Sollelis
- João Luiz Silva-Filho
- Matthias Marti
Royal Society (Wolfson Merit Award)
- Matthias Marti
European Research Council
- Teun Bousema
Wellcome Trust (209289/Z/17/Z)
- Abdirahman I Abdi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethical approval was granted by the Scientific Ethics Review Unit of the Kenya Medical Research Institute under the protocol; KEMRI/SERU/3149, and informed consent was obtained from the parents/guardian of the children.
Copyright
© 2023, Abdi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment
eLife 12:e85140.
https://doi.org/10.7554/eLife.85140
Further reading
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- Immunology and Inflammation
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Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf.
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The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS’s antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium’s own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.
