Plasmodium falciparum adapts its investment into replication versus transmission according to the host environment
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Curated by eLife
eLife assessment
This valuable work provides insight into how Plasmodium falciparum optimises the balance between infection of the human host and investment in onward transmission to the mosquito. Based on the appropriate and validated methodology most of the results are convincing, nonetheless, some conclusions are incomplete and require further support.
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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.
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eLife assessment
This valuable work provides insight into how Plasmodium falciparum optimises the balance between infection of the human host and investment in onward transmission to the mosquito. Based on the appropriate and validated methodology most of the results are convincing, nonetheless, some conclusions are incomplete and require further support.
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Reviewer #1 (Public Review):
Plasmodium falciparum must decide how much resources it will invest in within-host proliferation, or divert into gametocytogenesis to ensure onward transmission to the mosquito. The authors present here an interesting new perspective to this question using longitudinal data from a single study site over 18 years which covers three distinct transmission phases: pre-decline, decline and post-decline (which reflects a high malaria transmission setting declining to a low transmission setting). Laboratory studies in gametocyte commitment are having a renaissance in recent years, however in vivo studies have lagged behind. To address this knowledge gap, the authors have quantified the transcript levels in patient samples of ap2-g (a key player in gametocyte commitment), and PfSir2a (a gene hypothesised to sense …
Reviewer #1 (Public Review):
Plasmodium falciparum must decide how much resources it will invest in within-host proliferation, or divert into gametocytogenesis to ensure onward transmission to the mosquito. The authors present here an interesting new perspective to this question using longitudinal data from a single study site over 18 years which covers three distinct transmission phases: pre-decline, decline and post-decline (which reflects a high malaria transmission setting declining to a low transmission setting). Laboratory studies in gametocyte commitment are having a renaissance in recent years, however in vivo studies have lagged behind. To address this knowledge gap, the authors have quantified the transcript levels in patient samples of ap2-g (a key player in gametocyte commitment), and PfSir2a (a gene hypothesised to sense various cellular processes via metabolic regulation). They found that transcripts of both genes increase (indicating increased investment in gametocyte production) as transmission declines. Using the Luminex platform, they were then able to link gene expression directly to key inflammatory markers within the patient, showing that as malaria transmission declines, host inflammatory response changes. Adding greater depth, using unbiased lipidomics the authors then went on to link identified inflammatory response phenotypes to specific lipid species. Excitingly, they link depleted levels of host lysophosphatidylcholine (LPC) with a defined immune response state and increased gametocyte commitment in the low transmission setting. Taken together, this gives strong in vivo support for LPC as a key modulator in both parasite development and host immune response, something that to date has been mostly characterised in vitro.
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Reviewer #2 (Public Review):
The manuscript by Abdirahman I. Abdi et al. examines markers of host immunity and metabolism and markers of the malaria parasite (Plasmodium falciparum) growth and transmission. As the transmission of the malaria disease is governed by the sexual forms, (gametocytes), understating the commitment process represents a major step towards the global elimination of malaria. While the study focuses on a sound, very important topic in malaria research, its findings are partially based on rather weak evidence. In particular, in some parts there is a lack of adequate correlations, inaccurate statistics and misleading statistical tests. Moreover, these analyses are poorly explained, to a degree that some conclusions seem a bit enforced. In addition, the multitude of terms used makes it hard for the reader to follow …
Reviewer #2 (Public Review):
The manuscript by Abdirahman I. Abdi et al. examines markers of host immunity and metabolism and markers of the malaria parasite (Plasmodium falciparum) growth and transmission. As the transmission of the malaria disease is governed by the sexual forms, (gametocytes), understating the commitment process represents a major step towards the global elimination of malaria. While the study focuses on a sound, very important topic in malaria research, its findings are partially based on rather weak evidence. In particular, in some parts there is a lack of adequate correlations, inaccurate statistics and misleading statistical tests. Moreover, these analyses are poorly explained, to a degree that some conclusions seem a bit enforced. In addition, the multitude of terms used makes it hard for the reader to follow the text. The appeal of this study lies in its potential relevance to the global public health drive to eliminate malaria.
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Reviewer #3 (Public Review):
The authors present an association study geared to examine how epigenetic regulation of sexual commitment, immune responses and parasite growth change within a region that has undergone dramatic changes in transmission patterns over time. The work builds on previous epidemiological studies suggesting lower transmission settings result in parasites increasing sexual commitment, and most notably, examines mechanisms underlying these trends. The work shows the first in vivo association between LysoPC and gametocyte commitment (previously shown in vitro) in a large patient cohort. It also shows some very interesting trends relating LPC and parasite epigenetic markers to patient immune reactions.
The strengths of this paper include the use of a large patient cohort from a single geographic region, across distinct …
Reviewer #3 (Public Review):
The authors present an association study geared to examine how epigenetic regulation of sexual commitment, immune responses and parasite growth change within a region that has undergone dramatic changes in transmission patterns over time. The work builds on previous epidemiological studies suggesting lower transmission settings result in parasites increasing sexual commitment, and most notably, examines mechanisms underlying these trends. The work shows the first in vivo association between LysoPC and gametocyte commitment (previously shown in vitro) in a large patient cohort. It also shows some very interesting trends relating LPC and parasite epigenetic markers to patient immune reactions.
The strengths of this paper include the use of a large patient cohort from a single geographic region, across distinct transmission intensities - an intrinsically exciting way of studying.
The combination and integration of Luminex, RT-PCR, lipidomics, and clinical data provide a rich dataset for understanding host and parasite factors and provide novel in vivo evidence to support a role for LysoPC in commitment to gametocytogenesis.In terms of weaknesses, by its nature as an association study it is difficult to ascribe causation to the patterns of seen. However, the work is built around testing of clearly defined hypothesis (based on both in vitro and clinical data) and has enabled the development of sound and exciting models for testing in future work.
The work is well-designed and written, and the conclusions fully align with the data presented. The one minor contention with the description of data is the discussion of Fig 4C-E. The manuscript states "Indeed, LPC species showed a negative association with both ap2-g and Pfsir2a transcription levels (Fig.4C-E). The association was only significant in our data when inflammation is highest (and LPC level lowest), which is at low transmission (i.e., post decline)." There is in fact only an association in post decline samples and very clearly no association pre decline. This could be made clearer here and also in the discussion (L217). This is a minor point of clarity - the work remains a compelling addition to our understanding of sexual commitment of malaria parasites.
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