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Abstract
The causative agent of Chagas disease undergoes drastic morphological and biochemical modifications as it passes between hosts and transitions from extracellular to intracellular stages. The osmotic and mechanical aspects of these cellular transformations are not understood. Here we identify and characterize a novel mechanosensitive channel in Trypanosoma cruzi (TcMscS) belonging to the superfamily of small-conductance mechanosensitive channels (MscS). TcMscS is activated by membrane tension and forms a large pore permeable to anions, cations, and small osmolytes. The channel changes its location from the contractile vacuole complex in epimastigotes to the plasma membrane as the parasites develop into intracellular amastigotes. TcMscS knockout parasites show significant fitness defects, including increased cell volume, calcium dysregulation, impaired differentiation, and a dramatic decrease in infectivity. Our work provides mechanistic insights into components supporting pathogen adaptation inside the host, thus opening the exploration of mechanosensation as a prerequisite for protozoan infectivity.
Highlights
Mechanosensation is a universal characteristic of all cells, from bacteria to mammals (Cox et al, 2018; Arnadottir and Chalfie, 2010)
Sequence analysis and structural features of TcMscS predicted by homology model Analysis of Trypanosoma databases revealed the presence of a putative mechanosensitive channels (MscS)-like ion channel (TcCLB.504171.40) in the Esmeraldo-like haplotype of the T. cruzi CL Brener strain genome (TcMscS)
TcMscS, a novel mechanosensitive channel found in T. cruzi, is required for growth, calcium homeostasis, differentiation, and infectivity
Summary
Mechanosensation is a universal characteristic of all cells, from bacteria to mammals (Cox et al, 2018; Arnadottir and Chalfie, 2010). In Chlamydomonas, yeast, and various higher plants, the mechanisms of volume adjustment, stress relief, biogenesis, and maintenance of intracellular organelles such as plastids are regulated by mechanosensitive channels (Palmer et al, 2001; Lee et al, 2016; Peyronnet et al, 2008; Haswell and Meyerowitz, 2006) These channels belonging to the prokaryotic small-conductance mechanosensitive channel (MscS) family act as ubiquitous turgor regulators and osmolyte release valves in bacteria (Martinac et al, 1987; Sukharev et al, 1994; Levina et al, 1999) and archaea (Kloda and Martinac, 2001). Gene targeting by CRISPR/ Cas methods generated knockout and knockdown parasites that exhibit impaired growth and inability to robustly regulate cell volume These parasites show abnormal calcium regulation and a dramatic decrease in differentiation rate and infectivity, supporting the essential role of mechanosensitive channels in T. cruzi. Homologs are involved in the sensing of mechanical forces generated during tissue migration and cell penetration, stabilizing pressure gradients and relieving mechanical membrane stresses during cell volume regulation and developmental transitions
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