Babesia divergens egress from host cells is orchestrated by essential and druggable kinases and proteases

Author:

Elsworth Brendan1,Keroack Caroline1,Rezvani Yasaman2,Paul Aditya1ORCID,Barazorda Keare1,Tennessen Jacob1,Sack Samantha1,Moreira Cristina1,Gubbels Marc-Jan3,Meyers Marvin4,Zarringhalam Kourosh2,Duraisingh Manoj1ORCID

Affiliation:

1. Harvard T.H. Chan School of Public Health

2. University of Massachusetts Boston

3. Boston College

4. Saint Louis University

Abstract

Abstract Apicomplexan egress from host cells is fundamental to the spread of infection and is poorly characterized in Babesia spp., parasites of veterinary importance and emerging zoonoses. Through the use of video microscopy, transcriptomics and chemical genetics, we have implicated signaling, proteases and gliding motility as key drivers of egress by Babesia divergens. We developed reverse genetics to perform a knockdown screen of putative mediators of egress, identifying kinases and proteases involved in distinct steps of egress (ASP3, PKG and CDPK4) and invasion (ASP2, ASP3 and PKG). Inhibition of egress leads to continued intracellular replication, indicating exit from the replication cycle is uncoupled from egress. Chemical genetics validated PKG, ASP2 and ASP3 as druggable targets in Babesia spp. All taken together, egress in B. divergens more closely resembles T. gondii than the more evolutionarily-related Plasmodium spp. We have established a molecular framework for biological and translational studies of B. divergens egress.

Publisher

Research Square Platform LLC

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