TLR2 and endosomal TLR-mediated secretion of IL-10 and immune suppression in response to phagosome-confined Listeria monocytogenes

Autor: Mandy I. Cheng, Alfredo Chávez-Arroyo, Maria Krasilnikov, Daniel A. Portnoy, Alexander Louie, Brittney N. Nguyen
Rok vydání: 2020
Předmět:
Physiology
Pathology and Laboratory Medicine
medicine.disease_cause
Biochemistry
Mice
chemistry.chemical_compound
Phagosomes
Immune Physiology
Mobile Genetic Elements
Medicine and Health Sciences
Listeriosis
Biology (General)
Immune Response
Phagosome
Innate Immune System
0303 health sciences
Toll-Like Receptors
030302 biochemistry & molecular biology
Genomics
Acquired immune system
Interleukin-10
Bacterial Pathogens
Cell biology
Medical Microbiology
Cytokines
Pathogens
Research Article
QH301-705.5
Lipoproteins
Immunology
Endosomes
Immune Suppression
Microbiology
03 medical and health sciences
Genetic Elements
Signs and Symptoms
Immune system
Listeria monocytogenes
Lipoprotein Secretion
Diagnostic Medicine
Immunity
Virology
Immune Tolerance
Genetics
medicine
Animals
Secretion
Microbial Pathogens
Molecular Biology
030304 developmental biology
Transposable Elements
Biology and Life Sciences
Proteins
Molecular Development
RC581-607
Listeria Monocytogenes
Toll-Like Receptor 2
Mice
Inbred C57BL
TLR2
chemistry
Immune System
Parasitology
Peptidoglycan
Immunologic diseases. Allergy
Physiological Processes
Developmental Biology
Zdroj: PLoS Pathogens, Vol 16, Iss 7, p e1008622 (2020)
PLoS Pathogens
ISSN: 1553-7374
Popis: 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.
Author summary Listeria monocytogenes is a Gram-positive bacterial pathogen that has shown promise as a vaccine-delivery vector because of its ability to stimulate a robust T-cell response. The efficacy of a vaccine is in part tied to how well it avoids inducing the immunosuppressive cytokine IL-10. In this work, 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. We identified TLR2 and Unc93b1-dependent nucleic-acid-sensing Toll-like receptors as the primary host mediators of IL-10 secretion and immunosuppression. Unc93b1-dependent TLRs likely recognize nucleic acids released upon bacterial lysis in phagosomes. Strategies that reduce lytic death of bacteria and subsequent recognition of nucleic acids by endosomal TLRs could be used to improve bacteria-based vaccines.
Databáze: OpenAIRE
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