Inflammasome-Mediated Inhibition of Listeria monocytogenes-Stimulated Immunity Is Independent of Myelomonocytic Function

Cassandra R Williams,Michael L Dustin,John-Demian Sauer,Nancy E Freitag

doi:10.1371/journal.pone.0083191

Abstract

Activation of the Nlrc4 inflammasome results in the secretion of IL-1β and IL-18 through caspase-1 and induction of pyroptosis. L. monocytogenes engineered to activate Nlrc4 by expression of Legionella pneumophilia flagellin (L. monocytogenes L.p.FlaA) are less immunogenic for CD8+ T cell responses than wt L. monocytogenes. It is also known that IL-1β orchestrates recruitment of myelomonocytic cells (MMC), which have been shown to interfere with T cell-dendritic cells (DC) interactions in splenic white pulp (WP), limiting T cell priming and protective immunity. We have further analyzed the role of MMCs in the immunogenicity of L. monocytogenes L.p.FlaA. We confirmed that MMCs infiltrate the WP between 24–48 hours in response to wt L. monocytogenes infection and that depletion of MMCs enhances CD8+ T cell priming and protective memory. L. monocytogenes L.p.FlaA elicited accelerated recruitment of MMCs into the WP. While MMCs contribute to control of L. monocytogenes L.p.FlaA, MMC depletion did not increase immunogenicity of L.p.FlaA expressing strains. There was a significant decrease in L. monocytogenes L.p.FlaA in CD8α+ DCs independent of MMCs. These findings suggest that limiting inflammasome activation is important for bacterial accumulation in CD8α+ DCs, which are known to be critical for T cell response to L. monocytogenes.

Highlights

Pattern recognition receptors (PPR) are germ-line encoded components of innate immunity that bind various conserved microbial components such as lipopolysaccharide (LPS), lipoproteins, lipoteichoic acid (LTA), peptidoglycan and flagellin, collectively referred to as pathogen-associated molecular patterns (PAMPs) [1]
We found that upon infection with L. monocytogenes, myelomonocytic cells (MMC) steadily infiltrated into splenic white pulp (WP), creating a focus of MMC infiltration around the central arteriole (Figure 1A)
Because of the role that MMCs play in bacterial containment and their recently described attenuation of T cell activation by contacts made with dendritic cells (DC) [18,19,20], we hypothesized that MMCs played a role in the virulence defect seen in L. monocytogenes L.p.FlaA

Summary

Introduction

Pattern recognition receptors (PPR) are germ-line encoded components of innate immunity that bind various conserved microbial components such as lipopolysaccharide (LPS), lipoproteins, lipoteichoic acid (LTA), peptidoglycan and flagellin, collectively referred to as pathogen-associated molecular patterns (PAMPs) [1]. A subset of NLR family proteins has been shown to assemble into an inflammasome complex leading to the activation of caspase-1 [4]. One of the most well characterized inflammasomes, the Nlrc inflammasome ( known as Ipaf), activates caspase-1 in response to contamination of the cytosol with either bacterial flagellin or type III secretion inner rod proteins through receptors NAIP5 and NAIP2, respectively [6,7,8,9,10]. Chemokines and other endogenous inflammatory mediators leads to recruitment of innate immune cells such as neutrophils and monocytes that contribute to containing infection [11]

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