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Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death

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Science  08 Sep 2017:
Vol. 357, Issue 6355, pp. 1037-1041
DOI: 10.1126/science.aan0365

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  • RE: Sterilizing immunity by fungal apoptosis-like programmed death?

    With hopeful enthusiasm, I began reading Shlezinger et al., but soon questions arose that I could not resolve after some searching. The authors report that Aspergillus fumigatus undergoes apoptosis-like programmed cell death induced by lung neurtrophils. Key evidence comes from a pharmacologic approach. Purified fungal conidia and infected mice were treated with S12, a small molecule inhibitor of the "antiapoptotic" Aspergillus protein AfBIR1, leading to fungal cell death. However, it is difficult to find information about S12, a reported inhibitor of human Survivin, possibly by binding the BIR domain of Survivin (Ref 15). Is there evidence that S12 also binds and inhibits AfBIR1 or other fungal homologs of Survivin? AfBIR1 is a somewhat distant homolog with only one of two reported residues at positions essential for S12 binding (Ref 15). In turn, does AfBIR1 bind or inhibit fungal "caspases" as implied by the statement that Survivin "suppresses apoptosis by inhibiting caspase-3 and -7" (which remains in question at best)? Mammalian apoptosis is often defined in practice as caspase-3/-7-dependent cell death. Accordingly, the authors use a fluorescent caspase-3/-7 reporter. However, given that fungi do not encode true (aspartate-cleaving) caspases but instead encode metacaspases, which cleave after arginine, what biochemical process is responsible for the fungal "caspase activity" detected with the aspartate-containing substrate inhi...

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    Competing Interests: None declared.