Abstract
Listeria monocytogenes is a facultative intracellular bacterial pathogen that escapes from phagosomes and induces a robust adaptive immune response in mice, while mutants unable to escape phagosomes fail to induce a robust adaptive immune response and suppress the immunity to wildtype bacteria when co-administered. The capacity to suppress immunity can be reversed by blocking IL-10. In this study, we sought to understand the host receptors that lead to secretion of IL-10 in response to phagosome-confined L. monocytogenes (Δhly), with the ultimate goal of generating strains that fail to induce IL-10. We conducted a transposon screen to identify Δhly L. monocytogenes mutants that induced significantly more or less IL-10 secretion in bone marrow-derived macrophages (BMMs). A transposon insertion in lgt, which encodes phosphatidylglycerol-prolipoprotein diacylglyceryl transferase and is essential for the formation of lipoproteins, induced significantly reduced IL-10 secretion. Mutants with transposon insertions in pgdA and oatA, which encode peptidoglycan N-acetylglucosamine deacetylase and O-acetyltransferase, are sensitive to lysozyme and induced enhanced IL-10 secretion. A ΔhlyΔpgdAΔoatA strain was killed in BMMs and induced enhanced IL-10 secretion that was dependent on Unc93b1, a trafficking molecule required for signaling of nucleic acid-sensing TLRs. These data revealed that nucleic acids released by bacteriolysis triggered endosomal TLR-mediated IL-10 secretion. Secretion of IL-10 in response to infection with the parental strain was mostly TLR2-dependent, while IL-10 secretion in response to lysozyme-sensitive strains was dependent on TLR2 and Unc93b1. In mice, the IL-10 response to vacuole-confined L. monocytogenes was also dependent on TLR2 and Unc93b1. Co-administration of Δhly and ΔactA resulted in suppressed immunity in WT mice, but not in mice with mutations in Unc93b1. These data revealed that secretion of IL-10 in response to L. monocytogenes infection in vitro is mostly TLR2-dependent and immune suppression by phagosome-confined bacteria in vivo is mostly dependent on endosomal TLRs.
Highlights
Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that has been widely used as a model to study host immune responses
We investigated the bacterial and host factors that contribute to secretion of IL-10 and immunosuppression following infection with a strain of L. monocytogenes that cannot escape from host cell vacuoles
The goal of this study was to identify L. monocytogenes determinants that contribute to induction of IL-10 secretion from bone marrow-derived macrophages (BMMs)
Summary
Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that has been widely used as a model to study host immune responses. Infection of mice with L. monocytogenes induces the generation of adaptive immune responses that are protective against subsequent infection and are largely mediated by CD8+ T cells [1,2]. It has been posited that intracytosolic growth of L. monocytogenes is a prerequisite for the induction of T cell-mediated immunity because Δhly L. monocytogenes, which does not produce the virulence factor listeriolysin O and cannot escape phagocytic vacuoles, fails to induce robust protective immunity [7,8]. In 2009 Bahjat et al provided evidence that Δhly L. monocytogenes fails to induce robust protective immunity because it induces secretion of IL-10 early during infection. Strains that escape phagocytic vacuoles and grow in the cytosol induce generation of protective immunity in part because they avoid inducing IL-10-mediated suppression
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