Transmission (reproductive) strategies

Malaria parasites exhibit extensive variation throughout their infections in both investment in sexual stages (gametocytes) and the ratio of males to females (sex ratio). Furthermore, parasites alter these behaviours in response to changes in the in-host environment. Most of our research has focused on understanding why phenotypic plasticity in reproductive strategies has evolved and under what circumstances parasites should alter these behaviours.

 

P. berghei parasites mating in culture (credit: Sinclair Stammers)

Investment into sexual stages

Evolutionary theory predicts that parasites must balance their resource allocation between asexual replication and investment in gametocytes. Parasites must maximise their in-host survival in the face of attack from the immune response, competition and resource limitation, and their success is correlated to parasite numbers. At the same time, parasites must maximise opportunities to transmit to vectors by producing gametocytes, which requires investment into reproduction. Note, investment is not simply synonymous with the density or prevalence of gametocytes; the same relative level of investment can generate variation in gametocyte density due to differences in the density of the cohorts of asexual stages making decisions.

P. chabaudi gametocytes; blue female; pink male (credit: Sarah Reece)

Theory predicts that intermediate levels of investment in in-host survival are best; high investment occurs at the expense of transmission and increases the risk of host death, but low investment incurs the risk of parasite being cleared by hosts and results in a slow rate of transmission. Natural selection solves the trade-off between the rate and duration of transmission, which is mediated by virulence, to maximise lifetime transmission success (fitness): different circumstances require different solutions to this problem. However, in general, given that chronic infections make a major contribution to the infectious reservoir and vector availability is seasonal in many regions, a strategy of producing gametocytes “little and often” is likely to return greatest lifetime fitness in many populations (i.e. the value of early transmission is often outweighed by the sum of future transmission opportunities).

Female Anopheles stephensi resting (credit: Sarah Reece)

Parasites alter gametocyte investment in response to competition with con-specifics, changes in the availability of RBC resources, and treatment with anti-malarial drugs. Why they do this is yet to be resolved. We have proposed that parasites increase reproductive effort when conditions become stressful as an adaption to escape a potentially terminal situation (i.e. the infection is about to be cleared or host death is imminent). This strategy is called terminal investment and is supported by experiments showing that drug doses that severely reduce survival probability induce increased investment in gametocytes. And, when parasites experience less stressful situations, such as competition with conspecifics, resource limitation, or low doses of anti-malarial drugs they reduce investment (i.e. adopt reproductive restraint).

 

Investment in males versus females

Sex ratios in malaria parasites are generally female-biased and evolutionary theory predicts that sex ratios reflect the inbreeding rate. Because gametocytes taken up in a blood meal reflect the genetic composition of their host's infection, inbreeding occurs if mating groups consist of gametocytes from 1 or small number of genotypes, and outbreeding occurs when multiple genotypes are represented in the mating pool. 

P. berghei male gamete emerging from a male gametocyte (credit: Sinclair Stammers)

Female-biased sex ratios are expected when inbreeding occurs because this represents the most efficient allocation of resources to maximize the fertilization success of mating groups. Because each male can fertilise more than one female (each male can make up to 8 gametes), a female-biased sex ratio reduces competition for mates between related males and maximises the number of females available to be fertilised. In contrast, when infections are composed of several genotypes the greatest fitness returns come from increasing investment in male gametocytes. In this situation, a genotype that produces more males will have the greatest genetic representation in the next generation. We have revealed that parasites can evaluate the inbreeding rate they will experience in their vectors and adjust their gametocyte sex ratio accordingly. 

Anopheles stephensi blood feeding (credit: Sinclair Stammers)

However, whilst this theory explains why parasite sex ratios are usually female biased, it does not explain why sex ratios vary throughout infections in which the inbreeding rate does not change. For example, we have shown that sex ratios are adjusted in response to host anaemia and variation in gametocyte density. We have proposed that parasites adjust their sex ratio to compensate for reductions in their fertilisation success ('fertility insurance') due to a lack of males. When sex ratios are very female-biased and gametocyte density is low, or hosts are anaemic, there is a risk of too few males being taken up in blood meals to fertilise the females present. Furthermore, even if there are plenty of gametocytes, transmission-blocking immune factors impair the ability of males to make viable gametes, and the development of such immune factors may coincide with anaemia. 

P. mexicanum male gametocyte undergoing exflagellation to produce flagellated gametes (credit: Sinclair Stammers)

Therefore, in either of these scenarios, parasites must ensure their females are fertilised by investing in extra males (more than expected from their inbreeding rate alone). If levels of transmission-blocking immune factors and anaemia vary throughout infections, then the importance of a fertility insurance strategy will co-vary. 

Finally, we have demonstrated that sex ratios are important for parasite fitness: mating groups with slightly female biased sex ratios have the highest fertilisation success and extreme sex ratios are selected against (stabilizing selection).  More generally, this is first published experimental demonstration of how fitness varies over the range of sex ratios possible (i.e. from 0 - 100% males).


  (credit: EviMalar, Jamie Hall, Edward Ross, Wellcome Trust)

(credit: EviMalar, Jamie Hall, Edward Ross, Wellcome Trust)

What next?

We would like to know what information parasites use to make their reproductive decisions: how do they recognise unrelated strains in the host, and how do they know whether circumstances demand reproductive restraint or terminal investment, or fertility insurance?

We would also like to quantify how much fitness is enhanced by these parasite strategies. It may be possible to develop interventions that ‘trick’ parasites into suboptimal reproductive decisions for their fitness.