Advanced Search Abstract For vector-borne parasites such as malaria, how within- and between-host processes interact to shape transmission is poorly understood. In the host, malaria parasites replicate asexually but for transmission to occur, specialized sexual stages gametocytes must be produced.
Despite the central role that gametocytes play in disease transmission, explanations of why parasites adjust gametocyte production in response to in-host factors remain controversial. We propose that evolutionary theory developed to explain variation in reproductive effort in multicellular organisms, provides a framework to understand gametocyte investment strategies.
We examine why parasites adjust investment in gametocytes according to the impact of changing conditions on their in-host survival. We then outline experiments required to determine whether plasticity in gametocyte investment enables parasites to maintain fitness in a variable environment. Gametocytes are a target for anti-malarial transmission-blocking interventions so understanding plasticity in investment is central to maximizing the success of control measures in the face of parasite evolution.
Cycles of asexual replication inside host red blood cells RBCs , lasting from 24 to 72 hours [ 2 ], enable parasites to establish and maintain infections. To transmit to new hosts, every cell cycle a proportion of parasites develop into specialized sexual stages called gametocytes, which do not replicate in the host, but are infectious to the mosquito vector unlike asexual stages.
When taken up by the vector, male and female gametocytes differentiate into gametes and mate. The resulting offspring infect the vector and eventually produce stages infective to new hosts [ 3 ]. It is well known that the production of gametocytes varies during infections and across hosts [ 4—7 ]. However, the factors that induce commitment to produce gametocytes, and why parasites respond to these factors, are long-standing questions [ 8—11 ].
This information is central to understanding severity and transmission of disease, for predicting how disease control strategies will affect infectiousness [ 12—15 ], and may also reveal novel ways to target parasites. Here, we propose that malaria parasites strategically adjust investment into gametocytes hereafter, the conversion rate in response to the changeable conditions experienced during infections and that plasticity in the conversion rate enables parasites to optimize their survival and transmission during infections.
Our conceptual model stems from the integration of diverse experimental data into an ecological and evolutionary framework, thereby making the predictions of our model and its underlying assumptions explicit and testable.
While we focus on malaria parasites, the concepts and approach we outline can be applied more broadly to species for which in-host replication and between-host transmission are achieved by different specialized stages.
There is mounting evidence that traits underpinning in-host replication and between-host transmission spanning from immune evasion traits [ 16 , 17 ] to investment in transmissible forms [ 4 , 18 , 19 ] are adjusted by parasites during infections.
Phenotypic plasticity is an important solution to the challenges of life in a changing environment because it enables organisms to maintain fitness by altering their phenotype, through mechanisms such as differential gene expression, to match their circumstances [ 22 ]. Every cell cycle malaria parasites face a resource allocation trade-off between how much to invest in asexual stages that are required for in-host survival and in sexual stages that are essential for between-host transmission [ 23 , 24 ].
This is analogous to the trade-off between survival and reproduction faced by all sexually reproducing organisms [ 25 , 26 ]. Because reproduction is costly, phenotypic plasticity in the conversion rate influences two key fitness components: High conversion early in infections increases the potential for transmission, but this strategy risks insufficient investment in asexual stages to maintain the infection within the host, resulting in a short duration for transmission.
Conversely, excessive investment in asexual parasite replication reduces the rate of transmission at any given time, but this may be compensated for by longer infection durations and continued opportunities for transmission [ 24 , 27 ]. The number of gametocytes produced during infections is generally low [ 9 ] and it has been suggested that high densities of asexual stages are needed to shield gametocytes from transmission blocking immune responses [ 28 ].
However, this hypothesis does not explain why conversion rates vary during infections, between conspecific genotypes, and across species [ 7 , 37 , 39 ] Fig.
Therefore the conversion rate is not synonymous with the density or prevalence of gametocytes; variation in gametocyte densities can be generated by the same level of investment from different numbers of asexual stages [ 6 ]. Calculating conversion rates Current protocols for in vitro studies of P. The description of the biological process underlying the model in [ 6 ] overcomes challenges posed by hard-to-quantify parameters i.
Although the mathematical formulation assumes gametocytes are counted 24 hours into development, current molecular assays count gametocytes of an unknown age but are likely to be between 24 and 48 hours old.
Ideally we need to know the schedule of development and the precise point at which gametocytes are assayed, since these will determine the exact form of the conversion rate equation.