Redefining the role of autophagy in bacterial disease

PROJECT SUMMARY
In addition to traditional antimicrobials, targeting host defense pathways is an attractive strategy to limit the
adverse effect of bacterial infection. One such pathway that has received considerable attention is autophagy, a
process where cellular constituents are sequestered in a double-membrane vesicle that is subsequently targeted
to the lysosome for degradation and recycling. Autophagy is suggested to be critical for cell autonomous defense
because many bacterial pathogens are detected within double-membrane vesicles upon internalization, a
process referred to as xenophagy. Therefore, it is possible that drugs that target autophagy will be useful in a
wide range of diseases downstream of bacterial infections. In this program, we are studying the contribution of
ATG16L1, an autophagy protein that plays a central role in autophagosome formation, in the host response to
two model pathogens –Salmonella enterica Typhimurium and Staphylococcus aureus. By studying autophagy
in the setting of S. aureus we have discovered that ATG16L1 enable mammalian cells to respond to bacterial
infections by producing exosomes, small secreted vesicles that protect the host from infection by neutralizing
potent toxins produced by this bacterium. Our studies with Salmonella have discovered that the commonly found
ATG16L1 T300A allele impacts the susceptibility of the host towards this pathogen in a non-cell autonomous
manner. Thus, the goals of this competitive renewal application are to elucidate the mechanism(s) by which
mammalian cells coopt autophagy and pathogen sensing to control exosome biogenesis (Aim 1) and to unravel
the molecular details of how ATG16L1 T300A contributes to host-mediated protection from infection by bacterial
pathogens. A better understanding of how ATGs participate in non-xenophagy functions can help bridge the gap
between cell autonomous defense and complex extracellular mechanisms involved in host-microbe interactions.

Grant Number: 5R01AI121244-11
NIH Institute/Center: NIH
Principal Investigator: Ken Cadwell