Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans

Abstract

SUMMARY Apicomplexans invade a variety of metazoan host cells through mechanisms involving host cell receptor engagement and secretion of parasite factors to facilitate cellular attachment. We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. Using reverse genetic and chemical-genetic approaches, we determine that calcineurin critically regulates and stabilizes attachment of extracellular P. falciparum to host erythrocytes before intracellular entry and has similar functions in host cell engagement by T. gondii. Calcineurin-mediated Plasmodium invasion is strongly associated with host receptors required for host cell recognition and calcineurin function distinguishes this form of receptor-mediated attachment from a second mode of host-parasite adhesion independent of host receptors. This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans.

Calcium Builds Strong Host-Parasite Interactions

“…Depleting CnB in tightly synchronized blood stage P. falciparum parasites had no effect on intraerythrocytic development but had a very strong effect on erythrocyte invasion; CnA depletion had a similar impact (Paul et al, 2015). Critically, depletion of CnB had no impact on the exocytosis of invasion ligands from either micronemes or rhoptry organelles, even when CnB depletion was combined with drug inhibition to potentiate the effect in a chemical genetic approach.…”

“…By contrast, the role of the protein phosphatases that remove these moieties has remained largely unexplored. Two papers in this issue address this gap by performing detailed functional studies of the calcium-regulated protein phosphatase calcineurin (Paul et al, 2015;Philip and Waters, 2015).…”

“…In Plasmodium parasites, CnA and CnB are both expressed at multiple stages where host cell invasion occurs, indicating a possible invasion-related function. Paul et al (2015) and Philip and Waters (2015) used conditional genetic technologies to deplete the amount of CnA or CnB protein present in a cell and worked across multiple apicomplexan species to identify a very specific function for calcineurin during the invasion process.…”

“…In this issue of Cell Host & Microbe, Paul et al (2015) and Philip and Waters (2015) leverage experimental genetics to show that the calcium-regulated protein phosphatase, calcinuerin, regulates invasion in multiple parasite species.…”

Protein Kinase A Negatively Regulates Ca2+ signaling in Toxoplasma gondii

“…The phylum Apicomplexa comprises a group of obligate intracellular parasites that alternate 28 between intracellular replicating forms and actively motile extracellular forms that move of the glideosome and the release of adhesins from the micronemes 7,12,13 [14][15][16][17][18][19] .…”