A secreted helminth microRNA suppresses gastrointestinal cell differentiation required for innate immunity
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Abstract
Pathogens have developed multiple strategies to modulate host immune defense mechanisms. Understanding how this is achieved has potential to inform novel therapeutics for diseases caused by immune dysfunction. Parasitic helminths are masters of immune evasion, via release of secreted products, resulting in chronic infection. Helminths secrete small regulatory microRNA (miRNAs), which can interact with host cells. Here we show that a single parasite miRNA (miR-5352), conserved across gastrointestinal (GI) nematodes, suppresses IL-13-induced GI epithelial cell differentiation and cytokine responses, and promotes stem cell maintenance. Mechanistically, this is achieved through targeted repression of critical host factors, including Klf-4 and the IL-22 receptor, together with modulation of Wnt and Notch signalling pathways. Nematode miR-5352 shows seed sequence conservation with mammalian miR-92a family members, indicating that through convergent evolution, GI nematodes exploit a host miRNA regulatory network to suppress host innate responses, promote tissue regeneration and establish a favourable environment for chronic infection.
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show that a single GI nematode secreted miRNA can regulate host genes to promote stem cell maintenance, regeneration of host GI epithelial tissue and potentially reduce inflammation and immune cell migration.
Cool biology and cool paper- I enjoyed reading it!
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(F) Alignment of seed sequence (nucleotides 2-8) of miR-5352 sequences from GI nematode species (red) with mammalian (human, murine, bovine) miR-92a (purple).
since there is space, it would be nice to put a legend for the purple/red directly in the figure
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Merging bovine and ovine bioinformatic target prediction datasets for Hco-miR-5352 identified 54 potential target mRNAs,
Why do this? did the target predictions differ significantly between ovine and bovine?
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L-13 and miR-5352 mimic have opposing effects on gene expression in ovine abomasal organoids.
It might help get your point across/ be easier to interpret/learn from this figure if you 1) layered the functional enrichment analysis that you do on your differentially expressed genes in the next section onto this figure or 2) added some kind of functional grouping/color coding onto the gene names in all of these heatmaps. Otherwise, these heatmaps are pretty uninformative unless the reader knows offhand what all of these genes are, and would be just as good as a supp table. I think figures 4 and 5 would be more effective combined.
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Similarly, murine SI Dclk1 tdTomato reporter organoids stimulated with IL-13 and transfected with miR-5352 showed a reduced number of tdTomato+ cells relative to IL-13 plus control mimic, indicating suppression of murine tuft cell differentiation
what is the bioinformatically-predicted target mRNA of miR-5352 in mice? is it also KLF4?
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Our data indicate that H. contortus total ES suppresses IL-13 induced secretory cell development in both murine and ovine GI organoids.
Is this surprising? if the parasite has evolved a miRNA to specifically modulate host defense systems, would you have predicted this to be effective in a non-host system and different cell type (if the immune pathway is conserved)? It might be nice to comment here on whether this result suggests a target with high sequence conservation between mice/sheep
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oids. For this, we employed murine SI organoids in which tdTomato was expressed under the control of the promoter of the tuft cell-associated gene Dclk1
could you provide a little more context in this section to clarify the differences/advantages of the two organoid systems? I think it would help your paper be more clear to a broader audience.
for example, are gastric tuft cells and SI tuft cells equally relevant to H. contortus biology? Is the purpose of these two organoid systems to look at multiple points along the GI tract, or to show that the effects of the ES are conserved across species or just to take advantage of the ability to use a reporter system in the murine organoid? Does H. contortus ever infect mice?
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ES together with IL-13.
I see it in your methods, but it might be nice to also note here that you are using recombinant murine and ovine IL-13
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