A novel mechanosensitive channel controls osmoregulation, differentiation and infectivity in Trypanosoma cruzi

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    Evaluation Summary:

    The authors found a mechanosensitive channel gene in T. cruzi, and aimed to characterize its functions. The authors provide conclusive evidence that TcMscS is a mechanosensitive channel. They also show that TcMscS has additional roles outside of mechanosensation, likely playing a role in the infectivity of T. cruzi.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

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Abstract

Trypanosoma cruzi , 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 T. 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 of protozoan infectivity.

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  1. Author Response:

    Reviewer #2:

    Recommendations:

    A) In the section 'Electrophysiological characterization of TcMscS', the authors present compelling evidence that TcMscS gates in response to tension in the membrane. However, it is unclear, both in the text and the caption, if the trace shown in Figure 2 panel C was collected under tension. If it was, please include the applied pressure value in either the text or caption. Additionally, within this section the applied pressure to the patch is frequently unclear. One way to clear this up would be to 1- add the applied pressure to each trace or to 2- add the applied pressure for each patch to the figure caption. -In Panel E: can you comment on the conductance of the channels in the three traces? Why do you see channels that are approximately 1/2 the size of the first trace in the second …

  2. Reviewer #3 (Public Review):

    This manuscript investigates the structure, electrophysiological and biological functions of a novel mechanosensitive channel from the parasitic protist Trypanosoma cruzi. The channel was identified bioinformatically as being significantly related in sequence to known mechanosensitive channels of the McsS superfamily. Studies on channel proteins in pathogenic protists such as trypanosomes are limited, and this investigation focuses on a previously unstudied mechanosensitive channel which is of potential interest to parasite biology, because trypanosomes are subjected to various mechanical stress forces during their life cycles.

    Analysis of the sequence of the TcMscS protein by bioinformatics and structural prediction concludes that it is relatively divergent from previously studied members of the family from …

  3. Reviewer #2 (Public Review):

    In the manuscript 'A novel mechanosensitive channel controls osmoregulation, differentiation and infectivity in Trypanosoma cruzi' the authors show conclusive evidence that TcMscS is a mechanosensitive channel. They also show that TcMscS has additional roles outside of mechanosensation, likely playing a role in the infectivity of T. cruzi. This manuscript is well written with data that clearly supports the authors hypothesis. The evidence provided in the manuscript clearly shows that TcMscS gates in response to tension and that when knocked out of the genome there is a reduction in infectivity. This work will be impactful to both all researchers studying mechanosensation as it shows that mechanosensitive channels have roles outside of tension sensation.

    Recommendations:

    A) In the section …

  4. Reviewer #1 (Public Review):

    The authors found a mechanosensitive channel gene in T. cruzi, and aimed to characterize the functions. The strength of this manuscript is that the channel has been examined from various aspects: the modelled molecular structures; expression and localization during development; electrophysiological characteristics; cell motility; responses to osmotic stress; regulation of Ca2+ homeostasis; infectivity to host cells. The weakness of this study is the assessment of motility and the nature of the recombinant protein. To conclude, this study provides data sufficient for reporting the discovery and initial characterization of the novel mechanosensitive in T. cruzi. The most significant finding is the correlation with infection, but the involvement in the response to osmotic stress is also interesting in the field …

  5. Evaluation Summary:

    The authors found a mechanosensitive channel gene in T. cruzi, and aimed to characterize its functions. The authors provide conclusive evidence that TcMscS is a mechanosensitive channel. They also show that TcMscS has additional roles outside of mechanosensation, likely playing a role in the infectivity of T. cruzi.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)