1. Reviewed by eLife

    Reviewer #3 (Public Review):

    The authors set out to determine the role of interleukin (IL)-33 in the host immune response to the parasite Toxoplasma gondii. They achieve this using a mouse model of infection and a range of genetically modified mice to systematically prove the pathway involved.

    A major strength of the study is the use of strategic immune cell/factor-deficient mice in combination with recombinant proteins in vivo. This may be further strengthened by future studies that test the impact off inhibitory antibodies against the primary factor of interest, IL-33. This would allow for a loss and gain of function approach, supporting the exisiting in vivo data with recombinant mouse IL-33.

    Overall, the approach taken achieves the goal of the study. The manuscript is well written and systematically addresses the steps in the pathway that are required to mount an effective IL-33-mediate immune response to T. gondii.

    The likely impact of this work are new knowledge of the function of IL-33 in response to infection and the interaction between different components of the immune system to achieve a balanced, context dependent response. The study does not highlight new methods or technical advances, but does provide important new information on immune responses to infection.

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  2. Reviewed by eLife

    Reviewer #2 (Public Review):

    The authors eloquently showed that IL-33 was produced from stromal cells following Toxoplasma infection and that the absence of IL-33 signaling resulted in increased parasitemia. In agreement with this observation, they found that exogenous IL-33 reduced parasite load and increased the recruitment of inflammatory monocytes that are critical for resistance. The manuscript is well written and data presented here supports the major findings of this work.

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  3. Reviewed by eLife

    Reviewer #1 (Public Review):

    In initial experiments, low levels of IL-33 were detected in Toxaplasma-infected mice. How do these levels compare with normal physiological levels? It would help the reader to understand the relative levels to expect.

    The authors identify that most IL-33 is produced by stromal cells rather than hematopoietic cells. The frequency of tdTomato parasites appear to be much less than for the distribution of IL-33 producing cells. Does the parasite expression reflect 100% of parasites or are the number of IL-33-producing stromal cells stimulated in the infection much larger than the identifiable parasite number? That is, is the activation of the stromal cells a direct effect of the Toxaplasma infection or does it depend on intermediates to amplify the effect?

    Although the data presented are interesting and the authors identify that both stromal cells and hematopoietic cells contribute to the protective effect of IL-33, it is somewhat confusing amongst the hematopoietic cells, which cells are really driving the response amongst those categorized as 'innate'. Within the hematopoietic compartment, a number of associations are delineated but the causal connections are less clear. The provision of exogenous cytokines indeed have the effect they show in their results, but it remains unclear to this reviewer, whether these effects directly act on the hematopoietic cells, or stromal cells which alone are not sufficient to contain the infection and thus develop a higher pathogen load confounding their contributions.

    This work would be strengthened significantly by delineating more clearly the contributions of each compartment. Currently, the correlations are modelled on the responses in the omentum and it would be useful to understand if this reflects the broader response.

    This work would benefit from a schematic to indicate how the authors believe the different cells are connected and which are the real drivers/where connections have been demonstrated in driving the immune response.

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  4. Reviewed by eLife

    Evaluation Summary:

    This study sheds new light on the function of an immune system protein termed interleukin (IL)-33 in response to parasite infection. The study provides information on alternative functions of this immune protein and details the path taken to achieve a beneficial immune response. This study is of interest to immunologists who deal with the host response to infection, particularly to parasites. Immunotherapies that enhance or inhibit IL-33 are in development. Understanding the role of this immune factor in a broad range of infections is important when considering future treatments that target this pathway.

    (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 #3 agreed to share their name with the authors.)

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  5. Published on bioRxiv

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