CelTOS, a novel malarial protein that mediates transmission to mosquito and vertebrate hosts

Summary The malarial parasite has two hosts in its life cycle, a vertebrate and a mosquito. We report here that malar- ial invasion into these hosts is mediated by a protein, designated cell-traversal protein for ookinetes and sporozoites (CelTOS), which is localized to micron- emes that are organelles for parasite invasive motility. Targeted disruption of the CelTOS gene in Plasmo- dium berghei reduced parasite infectivity in the mos- quito host approximately 200-fold. The disruption also reduced the sporozoite infectivity in the liver and almost abolished its cell-passage ability. Liver infec- tivity was restored in Kupffer cell-depleted rats, indicating that CelTOS is necessary for sporozoite passage from the circulatory system to hepatocytes through the liver sinusoidal cell layer. Electron micro- scopic analysis revealed that celtos -disrupted ooki- netes invade the midgut epithelial cell by rupturing the cell membrane, but then fail to cross the cell, indicating that CelTOS is necessary for migration through the cytoplasm. These results suggest that conserved cell-passage mechanisms are used by both sporozoites and ookinetes to breach host cellu- lar barriers. Elucidation of these mechanisms might lead to novel antimalarial strategies to block para- site's transmission.