Induction of the macrophage unfolded protein response (UPR) by MRSA infection enhances anti-microbial function

Project: Research

Investigators

  • Basel Hanna Abuaita (PI)

Description

The unfolded protein response (UPR) is triggered when the endoplasmic reticulum (ER) becomes stressed as a result of accumulation of unfolded protein in the lumen. It is an adaptive response that consists of signaling cascades that promote cellular recovery from such stress. One of the UPR sensors, inositol-requiring transmembrane kinase/ endonuclease 1 (IRE1) is selectively induced during bacterial infection and seems to benefit the host in eliminating the infection. However, the molecular mechanisms driving infection-induced IRE1 activation and function are poorly understood. Preliminary studies from our laboratory indicate that IRE1 activation occurs in macrophages upon infection by methicillin-resistant Staphylococcus aureus (MRSA), a pathogen that is the most common infectious cause of endocarditis. In addition, the IRE1 arm of the UPR seems to enhance macrophage anti-microbial activity. I hypothesize that IRE1 is activated through modulation of the ER luminal environment, leading to enhanced phagosome maturation and microbial killing. I propose the following aims to elucidate this hypothesis: 1) Define the mechanism of IRE1 activation by MRSA infection. 2) Identify the pathway by which IRE1 enhances macrophage anti-microbial activity. 3) Characterize the efficacy of small molecule IRE1 activators in enhancing MRSA killing. This work will identify new pathways that can be targeted to therapeutically enhance anti-microbial activity, and will also test a new class of drugs that may provide valuable adjunctive therapy for inhibiting MRSA-related disease, including endocarditis.
Award amount$95,224.00
Award date07/01/2013
Program typePostdoctoral Fellowship
Award ID13POST16360006
Effective start/end date07/01/201306/30/2015
StatusFinished