title: Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin.
abstract: 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 (Atg16L1(HM)), 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, Atg16L1(HM) 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.
authors: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016, USA.
authors: Katie
authors: K
authors: Maurer
authors: Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors: Tamara
authors: T
authors: Reyes-Robles
authors: Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA.
authors: Francis
authors: F
authors: Alonzo
authors: Department of Pathology, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors: Joan
authors: J
authors: Durbin
authors: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: victor.torres@nyumc.org.
authors: Victor J
authors: VJ
authors: Torres
authors: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: ken.cadwell@med.nyu.edu.
authors: Ken
authors: K
authors: Cadwell
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001427:Bacterial Toxins / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics; D006460:Hemolysin Proteins / Q000276:immunology*; D007108:Immune Tolerance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D018345:Mice, Knockout; D011023:Pneumonia, Staphylococcal / Q000276:immunology / Q000382:microbiology; D018805:Sepsis / Q000276:immunology / Q000382:microbiology; D016019:Survival Analysis
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D001427:Bacterial Toxins; D002352:Carrier Proteins; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin