Stress and sex in malaria parasites: Why does commitment vary?

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.

Keywords: Plasmodium; commitment; gametocyte; phenotypic plasticity; stress; transmission.

Figure 1.

Plasmodium conversion rates are variable. The conversion rate (±SEM) represents the proportion of a given cohort of asexual parasites that differentiate into sexual stage gametocytes. Variation in conversion is observed across species and during infections/culture (A). Note: conversion is calculated differently for rodent malaria parasites (P. chabaudi, P. yoelli, P. vinckei and P. berghei, in vivo) and for P. falciparum (in vitro) (see Box 1). Different conspecific genotypes of P. chabaudi, in the same experiment, exhibit different patterns for conversion during infections (B). Plasmodium chabaudi reduces conversion when experimentally exposed to in-host competition (C). The conversion rates of genotype AJ are illustrated; during a single genotype infection (alone), and the mean conversion when in competition with either genotypes ER, AS, or both together (in competition). The reduction in conversion observed when drug sensitive P. falciparum isolates are exposed in vitro to antimalarial drugs or control conditions (D) [7, 37, 39]

Figure 2.

Predicted pattern for conversion. (A) Under low ‘stress’ (e.g. early in infections of naïve hosts) parasites can afford to invest in gametocytes, but if conditions deteriorate and proliferation is constrained (e.g. when parasites face stressors such as anaemia, competition or immune responses) parasites reduce conversion, employing reproductive restraint (blue dashed lines), to ensure in-host survival and the potential for future transmission. The form that reproductive restraint takes could follow any of the patterns illustrated with the dashed blue lines, depending on a number of factors (e.g. the cues parasites respond to, how accurately survival probability is determined, and the value of future versus current transmission). When parasites face circumstances likely to be fatal (e.g. when their death rate exceeds the potential for replication during radical drug treatment) or host death is imminent (e.g. due to severe anaemia), parasites should make a terminal investment by investing remaining resources into gametocytes (red solid line). A switch point and step function between reproductive restraint and terminal investment is predicted because investing all remaining resources is the best option in a situation likely to be fatal. Note: the x-axis does not simply translate to ‘time since infection’ because the severity of different stressors fluctuates during infections. (B) Data suggest that parasites can detect and respond directly to individual stressors and also to the effect they have on proliferation rate. Information from the cues parasites use must be fed into the molecular pathways that underpin commitment to effect a gametocyte investment decision. (C) The total production of gametocytes (the area under the curve) is equal for both genotypes [14]. However, genotype A invests heavily into transmission early in the infection and therefore achieves higher gametocyte densities over a shorter period of time, whereas B has a lower relative investment in gametocytes at each time point, but achieves a longer period for transmission. The optimal balance between these two extremes is predicted to depend on many factors including the frequency of vector blood meals, and the chances of the host clearing the infection or dying