2006 Development of quantitative real-time tests to quantify gametocyte density for P. falciparum [12] and P. chabaudi [13]. In P. falciparum, submicroscopic density gametocytes are frequent follow-up treatments and these infections contribute significantly to transmission [12,21]. Previous beliefs, based on microscopic data, are that treatment may lead to an increased prevalence of gametocytes. Molecular testing shows that this peak in gametocyte prevalence after treatment reflects an increase in gametocyte density to levels more likely to be detected under a microscope [12,53]. In addition, artemisinin-based combination therapy (ACT) reduces gametocyte density and the proportion of infected mosquitoes, but does not affect the proportion of patients with infectious gametocytes (infectious reservoir) [12,21]. A better understanding of the factors influencing gametocyte investment and transmission is essential for the development and evaluation of clinical interventions that interfere with sexual reproduction in plasmodium.
For example, asymptomatic infectious persons are of great importance from a public health perspective. Identifying “gametocyte carriers” and factors that can lead to increased transmission was considered very important in determining sources of infection in a community. Given that many asymptomatic carriers contribute to transmission, it may be necessary to reconsider the feasibility and public health impact of targeted control on gametocytes, such as intermittent preventive therapy and mass therapy [23,76,77]. Particularly in areas with pronounced seasonal transmission, a reduction in the infectious reservoir over consecutive years could reduce the baseline reproduction rate (R0; the number of future cases of an infectious case at present) to a controllable level. However, a short-term limitation of this approach is the presence of drug-resistant parasites, which can overcome the effect of the drugs used and increase in frequency given the drug pressure [76, 77]. In order to establish malaria control strategies, transmission parameters, including prevalence and density of gametocytes after the intervention, should be evaluated and measures to control high gametocymia should be considered. Therefore, detection and quantification of molecular gametocytes should be added to existing protocols for the evaluation of control strategies, including the efficacy of antimalarial drugs [78]. In vertebrate hosts, malaria parasites produce specialized male and female sex stages (gametocytes). Shortly after being ingested by a mosquito, gametocytes rapidly produce gametes and, after mating, infect their vector and can be transferred to new hosts. Although gametocytes are the parasitic stages first identified (more than a century ago), they have remained elusive and fundamental questions about their biology remain. However, the post-genomic era has supported information on the specialized molecular machinery of gametocytogenesis and accelerated the development of molecular tools for the detection and quantification of gametocytes. The application of these highly sensitive and specific tools has opened up new approaches and provided new perspectives on gametocyte biology.
Here we review the findings of the past ten years, highlight unanswered questions and suggest new directions. Although our knowledge of gametocyte biology is not as advanced as that of asexual blood stages, the great interest of researchers in recent years has greatly deepened our understanding of gametocyte biology. Advances in gametocyte culture, isolation and purification, as well as the impressive amount of data from genome-wide analyses, proteomic studies and microarrays, have led to the identification of certain gametocytic stage specific antigens as well as sex-specific proteins that can be used as targets for malaria transmission and blocking intervention strategies. In addition, recent discoveries on the molecular mechanism of gametocyte binding have greatly improved our knowledge of how sexual differentiation is initiated and regulated in the malaria parasite. However, some questions about gametocyte biology still need to be answered. The mechanism by which stressors are perceived to increase gametocyte binding is not well understood. Some components of the gametocyte activation signaling cascade are still unknown, such as the receptor(s) responsible for signal perception after gametocyte activation by XA. How gametocyte sequestration takes place in the bone marrow and what molecular mechanism underlies this phenomenon need to be deciphered. In addition, a good understanding of the mechanism by which the gametocyte adapts rapidly once it is in the mosquito vector and the basis of fertilization is needed. In addition, not much is known about gametocyte metabolism.
Most metabolic pathways are not described. A good understanding of these aspects in gametocyte biology would greatly improve gametocyte control strategies. Asexual blood stage parasites produce the clinical form of malaria due to the destruction of erythrocytes during replication in the mammalian host. However, these asexual blood stages cannot be transferred to the mosquito to continue the parasite`s life cycle. Because of this, a subset of asexual blood stages is able to pass to the sexual pathway, which leads to the formation of sex progenitor cells, gametocytes. The process of passing from the asexual blood stage to gametocytes is called gametocyte binding. About 20% of all plasmodial genes are specifically expressed in sexual stages [45, 46].
