Mitochondrial ROS potentiates indirect activation of the AIM2 inflammasome

Deborah D Crane,Tara D Wehrly,Timothy J Bauler,Catharine M Bosio

doi:10.3389/fmicb.2014.00438

Abstract

Activation of the inflammasome is important for the detection and clearance of cytosolic pathogens. In contrast to avirulent Francisella novicida (Fn), infection with virulent Francisella tularensis ssp tularensis does not trigger activation of the host AIM2 inflammasome. Here we show that differential activation of AIM2 following Francisella infection is due to sensitivity of each isolate to reactive oxygen species (ROS). ROS present at the outset of Fn infection contributes to activation of the AIM2 inflammasome, independent of NLRP3 and NADPH oxidase. Rather, mitochondrial ROS (mROS) is critical for Fn stimulation of the inflammasome. This study represents the first demonstration of the importance of mROS in the activation of the AIM2 inflammasome by bacteria. Our results also demonstrate that bacterial resistance to mROS is a mechanism of virulence for early evasion of detection by the host.

Highlights

The innate immune system recognizes pathogen associated molecular patterns (PAMPs) using germline encoded pattern recognition receptors (PRRs) to initiate immune responses to pathogens
We first determined if SchuS4 activated the inflammasome in BONE MARROW DERIVED MACROPHAGES (BMM) and compared this response to cells infected with Francisella novicida (Fn)
Data presented demonstrate that mitochondrial ROS (mROS) indirectly contributes to the activation of the AIM2 inflammasome following Fn infection

Summary

Introduction

The innate immune system recognizes pathogen associated molecular patterns (PAMPs) using germline encoded pattern recognition receptors (PRRs) to initiate immune responses to pathogens. NOD-like receptors (NLR) and AIM2 are cytosolic PRRs that function as a scaffold to promote assembly of the inflammasome. The inflammasome is an innate immune signaling complex which activates caspase-1, resulting in cleavage of caspase-1 into two subunits, in response to intracellular pathogens and danger signals (Franchi et al, 2012). Activation of the inflammasome is essential for clearance of many intracellular bacteria including Shigella flexneri, Listeria monocytogenes, Legionella pneumophila, Salmonella typhimurium, and avirulent Francisella novicida (Fn; Mariathasan et al, 2005). It is suspected that the ability of fully virulent cytosolic pathogens, e.g., virulent F. tularensis ssp. Tularensis, to escape detection by the inflammasome is a critical component of virulence It is suspected that the ability of fully virulent cytosolic pathogens, e.g., virulent F. tularensis ssp. tularensis, to escape detection by the inflammasome is a critical component of virulence

Methods

Results

Conclusion