Professional phagocytes play a critical role in anti-microbial defense. Uptake of microbes by phagocytosis results in the formation of a dynamic vesicular compartment, termed the phagolysosome. The phagolysosome physically and functionally defines a critical separation of the microbe from the host cell, allowing the host to target degradative anti-microbial mechanisms to this confined space. We find that bacterial infection triggers the unfolded protein response (UPR), a cellular program associated with ER stress and innate immune function. Activation of the UPR increases the capacity of the cell to degrade proteins, but the mechanisms responsible for this degradation are incompletely understood. Our preliminary studies suggest that UPR activation during bacterial infection results in increased association of methicillin resistant Staphylococcus aureus (MRSA) with the degradative lysosomal compartment and bacterial killing. Inhibition of specific UPR regulators results in decreased association with lysosomes and decreased MRSA killing. The central hypothesis of this proposal is that activation of the UPR in phagocytes results in increased trafficking and degradative capacity of the phagolysosomal network, leading to enhanced degradative, and thus anti-microbial, function. To test this hypothesis, we will (1) measure mobilization of the lysosomal network using physical and functional markers upon activation of the UPR;(2) define the role of the UPR sensors, Ire1, ATF6 and PERK in regulating specific aspects of lysosomal trafficking and function in response to innate immune signals during infection. Regulation of the degradative capacity of the cell by the UPR is a fundamental strategy by which cells can respond to perturbations in the production or secretion of proteins. Our studies now highlight a novel connection between UPR-mediated degradation and anti-microbial function, and will define key druggable targets that shape the macrophage anti-microbial arsenal for development of anti-infective strategies.

Public Health Relevance

Virulent pathogens may evade host-antimicrobial defenses and are a major cause of morbidity and mortality worldwide. Our studies have revealed a fundamental cellular stress response that broadly enhances host defense, increasing killing of bacteria such as methicillin-resistant Staphylococcus aureus by immune cells. These findings highlight a new mechanism for anti-microbial defense that may provide potential targets for development of anti-infective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI101777-02
Application #
8519298
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$177,184
Indirect Cost
$59,684
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Abuaita, Basel H; O'Riordan, Mary X (2014) Listeria exploits damage and death to spread bad news. Trends Microbiol 22:370-1
Cassidy, Sara K B; O'Riordan, Mary X D (2013) More than a pore: the cellular response to cholesterol-dependent cytolysins. Toxins (Basel) 5:618-36