TY - JOUR
T1 - Autophagy mediates tolerance to staphylococcus aureus alpha-toxin
AU - Maurer, Katie
AU - Reyes-Robles, Tamara
AU - Alonzo, Francis
AU - Durbin, Joan
AU - Torres, Victor J.
AU - Cadwell, Ken
N1 - Funding Information:
We would like to thank Alejandra Mendoza and Susan Schwab for assistance with endothelial cell isolation, Michael Cammer for assistance with imaging, NYUSoM Flow Cytometry and Cell Sorting Center (5P30CA016087-33), NYUSoM IHC Core (supported in part by NYUCI center support grant P30 CA16087), and NYUSoM Microcopy Core (RR023704-01A1). This work was supported by US NIH grants R01 DK093668 (K.C.), Training Grant #5 T32 GM0738 (K.M.), AI100853 (K.M.), F30 DK098925 (K.M.); American Heart Association 12GRNT12030041 (K.C.); R01AI099394 (V.J.T.); R01AI105129 (V.J.T.); Training Grant T32 AI007180 (T.R.-R.); F31 AI112290 (T.R.-R.); and F32 AI098395 (F.A.). V.J.T. is a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/4/8
Y1 - 2015/4/8
N2 - Resistance and tolerance are two defense strategies employed by the host against microbial threats. Autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. Here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant Staphylococcus aureus USA300 is to mediate tolerance rather than resistance. Atg16L1 hypomorphic mice (Atg16L1HM), which have reduced autophagy, were highly susceptible to lethality in both sepsis and pneumonia models of USA300 infection. Autophagy confers protection by limiting the damage caused by α-toxin, particularly to endothelial cells. Remarkably, Atg16L1HM mice display enhanced survival rather than susceptibility upon infection with α-toxin-deficient S. aureus. These results identify an essential role for autophagy in tolerance to Staphylococcal disease and highlight how a single virulence factor encoded by a pathogen can determine whether a given host factor promotes tolerance or resistance.
AB - Resistance and tolerance are two defense strategies employed by the host against microbial threats. Autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. Here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant Staphylococcus aureus USA300 is to mediate tolerance rather than resistance. Atg16L1 hypomorphic mice (Atg16L1HM), which have reduced autophagy, were highly susceptible to lethality in both sepsis and pneumonia models of USA300 infection. Autophagy confers protection by limiting the damage caused by α-toxin, particularly to endothelial cells. Remarkably, Atg16L1HM mice display enhanced survival rather than susceptibility upon infection with α-toxin-deficient S. aureus. These results identify an essential role for autophagy in tolerance to Staphylococcal disease and highlight how a single virulence factor encoded by a pathogen can determine whether a given host factor promotes tolerance or resistance.
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U2 - 10.1016/j.chom.2015.03.001
DO - 10.1016/j.chom.2015.03.001
M3 - Article
C2 - 25816775
AN - SCOPUS:84926656919
SN - 1931-3128
VL - 17
SP - 429
EP - 440
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -