Modulation of CRK1 kinase in Trypanosoma cruzi: Functional role and impact on benznidazole resistance

• Grant number: 24/23849-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2025
• End date: October 31, 2028
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Simone Guedes Calderano
• Grantee: Artur da Paixão Corrêa
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Chagas disease is one of the major neglected diseases in South America, caused by the flagellate protozoan Trypanosoma cruzi, discovered in 1909 by the physician and researcher Carlos Chagas. T. cruzi has a complex life cycle, alternating between forms specialized in replication and infection, with the transition between these forms influenced by various environmental factors such as pH, osmolarity, ionic composition, and nutrient availability. Although the pathways involved in the cellular changes observed during transitions between the evolutionary forms of T. cruzi are not fully understood, it is known that in trypanosomatids, Cdc2-Related Kinases (CRKs) are responsible for regulating the cell cycle in replicative forms of the parasite. Furthermore, dormancy in T. cruzi appears to be closely associated with the control of cell proliferation in amastigotes, functioning as an adaptive response to adverse conditions, such as DNA damage caused by the chemotherapeutic agent benznidazole. This triggers the parasite to activate checkpoint mechanisms, temporarily halting replication to preserve its genetic integrity and ensure survival. Therefore, considering that the protein kinase CRK1 regulates the cell cycle in Trypanosoma cruzi and is present in all evolutionary forms, this study will investigate its role in the transition between replicative and dormant states. These processes are critical to benznidazole resistance, as dormancy in amastigotes, characterized by halted cell replication and reduced metabolism, protects the parasites from treatment. Thus, the characterization of CRK1 and its regulatory pathways could unveil key mechanisms, contributing to the identification of new therapeutic targets. (AU)