Extended Data Fig. 5: Model of the Babesia divergens lytic cycle.

1. An extrinsic signal (calcium) or an intrinsic signal activates guanylate cyclase (GC) and/or inhibits a phosphodiesterase (PDE). 2. The increased cGMP levels activate cGMP-dependent kinase (PKG), which leads to the release of calcium. 3. Calcium, CDPK activity and potentially unknown signals lead to the fusion of micronemes to the parasite plasma membrane. 4. The contents of the micronemes, which have been proteolytically matured by ASP3, are released into the RBC cytosol, including lytic factors, and invasion ligands onto the parasite surface. 5. Lytic factors act to permeabilize the RBC membrane. The permeabilized RBC membrane allows an influx of calcium, acting as a positive feedback loop. 6. Unknown signals, potentially including PKG, lead to the activation of adenylate cyclase (AC) and/or inhibition of a PDE, which increases cAMP levels. The increased cAMP activates PKAc1, which is putatively required for invasion. PKAc1 activity also putatively reduces egress, potentially through inhibition of the PKG signaling pathway. Solid lines represent pathways with a high confidence based on available data for B. divergens. Dashed lines indicate processes based primarily on the RNAseq and small molecule inhibitors data from this paper and orthology to P. falciparum or T. gondii.