Preparing for Transmission: Gene Regulation in Plasmodium Sporozoites

Abstract

Plasmodium sporozoites are transmitted to mammals by anopheline mosquitoes and first infect the liver, where they transform into replicative exoerythrocytic forms, which subsequently release thousands of merozoites that invade erythrocytes and initiate the malaria disease. In some species, sporozoites can transform into dormant hypnozoites in the liver, which cause malaria relapses upon reactivation. Transmission from the insect vector to a mammalian host is a critical step of the parasite life cycle, and requires tightly regulated gene expression. Sporozoites are formed inside oocysts in the mosquito midgut and become fully infectious after colonization of the insect salivary glands, where they remain quiescent until transmission. Parasite maturation into infectious sporozoites is associated with reprogramming of the sporozoite transcriptome and proteome, which depends on multiple layers of transcriptional and post-transcriptional regulatory mechanisms. An emerging scheme is that gene expression in Plasmodium sporozoites is controlled by alternating waves of transcription activity and translational repression, which shape the parasite RNA and protein repertoires for successful transition from the mosquito vector to the mammalian host.

Keywords: Plasmodium; gene regulation; malaria; quiescence; sporozoite; transcription; translational repression.

Figure 1

Overview of the Plasmodium life cycle and the gene regulation mechanisms controlling parasite transmission from the mosquito vector to the mammalian host. During blood feeding on an infected host, female anopheline mosquito ingest male and female gametocytes (1), which transform into male and female gametes in the insect midgut lumen, followed by fertilization (2) and formation of motile ookinetes that cross the midgut epithelium and transform into extracellular oocysts. Oocysts undergo intense parasite replication (3) until releasing thousands of immature sporozoites that traffic to the salivary glands and mature into infectious sporozoites (4). In the salivary glands, sporozoites persist in a poised state for several days or weeks (5), awaiting transmission, which occurs when the mosquito feeds for blood on a new host. Infectious sporozoites are injected in the host skin and migrate to the liver, where they invade hepatocytes (6) and transform into replicative exoerythrocytic forms (EEFs) (7). In species such as P. vivax, some of the parasites do not replicate immediately after invasion but, instead, transform into dormant stages called hypnozoites (8). Parasite replication in the liver culminates with the release of thousands of merozoites into the circulation, which invade erythrocytes and initiate the asexual blood stage cycle (9). Individual factors with functional evidence for a role in transcriptional or post-transcriptional gene regulation during sporozoite development, maturation, or establishment of infection in the liver are indicated.

Figure 2

Transcriptional, post-transcriptional and translational regulators in Plasmodium sporozoites. (A) Number of transcriptional-associated proteins (TAPs), based on the classification of Bischoff and Vaquero (2010). Black bars represent proteins with mass spectrometry evidence in Plasmodium spp. sporozoites. Gray bars represent proteins not detected in sporozoites by mass spectrometry. For details on protein identity and mass spectrometry results, see Table S1 . (B) Number of post-transcriptional and translational regulators, based on the classification of Reddy et al. (2015) and Bennink and Pradel (2019). Black bars represent proteins with mass spectrometry evidence in Plasmodium spp. sporozoites. Grey bars represent proteins not detected in sporozoites by mass spectrometry. For details on protein identity and mass spectrometry results, see Table S2 .