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.
Reviewing Editor
- Urszula Krzych, Walter Reed Army Institute of Research, United States
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.
Version history
- Received: November 24, 2022
- Preprint posted: December 2, 2022 (view preprint)
- Accepted: March 1, 2023
- Accepted Manuscript published: March 14, 2023 (version 1)
- Version of Record published: March 29, 2023 (version 2)
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.
Metrics
-
- 1,801
- views
-
- 371
- downloads
-
- 10
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Microbiology and Infectious Disease
Survival of Mycobacterium tuberculosis within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3′,5′-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including M. tuberculosis. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of rv0805 PDE, and absence of phoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.
-
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single-domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here, we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast et al., 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.
