Biology of Malaria Transmission

Abstract

Understanding transmission biology at an individual level is a key component of intervention strategies that target the spread of malaria parasites from human to mosquito. Gametocytes are specialized sexual stages of the malaria parasite life cycle developed during evolution to achieve crucial steps in transmission. As sexual differentiation and transmission are tightly linked, a deeper understanding of molecular and cellular events defining this relationship is essential to combat malaria. Recent advances in the field are gradually revealing mechanisms underlying sexual commitment, gametocyte sequestration, and dynamics of transmissible stages; however, key questions on fundamental gametocyte biology still remain. Moreover, species-specific variation between Plasmodium falciparum and Plasmodium vivax transmission dynamics pose another significant challenge for worldwide malaria elimination efforts. Here, we review the biology of transmission stages, highlighting numerous factors influencing development and dynamics of gametocytes within the host and determinants of human infectiousness.

Figure 1.

The Plasmodium falciparum life cycle in the human host. (A) Life cycle of P. falciparum. Human malaria infection is initiated when a female anopheline mosquito injects Plasmodium sporozoites into the skin during a blood meal. Sporozoites actively reach peripheral circulation and migrate to the liver in which they replicate within hepatocytes forming merozoites that are released into the bloodstream. Merozoites invade red blood cells (RBCs) and develop through ring, trophozoite, and schizont stages before forming new merozoites that are released at schizont egress and reinvade new RBCs. A small proportion of blood stage parasites develop into sexual stages called gametocytes that reach the dermis where they are taken up by another mosquito. After fertilization and sporogonic development in the mosquito midgut, infectious sporozoites are formed that reach the salivary glands for transmission into another host. (B) Schematic representation of P. falciparum gametocyte developmental stages. Gametocytes undergo five distinct morphological stages during development. Stage I and early stage II are morphologically similar to early stage asexual parasites, and late stage II is the first stage that can be distinguished from asexual trophozoites. Late stage III and stage IV are further elongated and characterized by their spindle shape, whereas in stage V gametocytes, the ends are more rounded forming a crescent shape with minimal visible host cell surface. (C) Model of bone marrow sequestration of P. falciparum gametocytes. Sexually committed parasitized RBCs home to the bone marrow by binding to endothelial wall of sinusoids followed by transmigration into the extravascular space and undergo development. Alternatively, early asexual parasite stages transmigrate into the extravascular space to produce sexually committed schizonts that release merozoites, which, on reinvasion, begins sexual developmental stages (models also reviewed in Nilsson et al. 2015). Increased rigidity of early gametocytes (Aingaran et al. 2012; Peatey et al. 2013) and the observed binding of immature gametocytes to erythroblastic islands (Joice et al. 2014) favor their maturation in the hematopoietic system. Mature gametocytes exit the microenvironment potentially because of restoration in their deformability (Tiburcio et al. 2012) and intravasate into circulation to be taken up by mosquitoes. (D) Model of P. falciparum gametocyte localization to the skin. Mature gametocytes preferentially sequester in the subdermal micro capillaries of skin where they are easily accessible to mosquito during a blood meal. (Inset) Factors influencing malaria transmission including host, parasite, and environmental conditions are listed.