Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis.

Recent studies have implicated a family of mammalian Toll-like receptors (TLR) in the activation of macrophages by Gram-negative and Gram-positive bacterial products. We have previously shown that different TLR proteins mediate cellular activation by the distinct CD14 ligands Gram-negative bacterial LPS and mycobacterial glycolipid lipoarabinomannan (LAM). Here we show that viable Mycobacterium tuberculosis bacilli activated both Chinese hamster ovary cells and murine macrophages that overexpressed either TLR2 or TLR4. This contrasted with Gram-positive bacteria and Mycobacterium avium, which activated cells via TLR2 but not TLR4. Both virulent and attenuated strains of M. tuberculosis could activate the cells in a TLR-dependent manner. Neither membrane-bound nor soluble CD14 was required for bacilli to activate cells in a TLR-dependent manner. We also assessed whether LAM was the mycobacterial cell wall component responsible for TLR-dependent cellular activation by M. tuberculosis. We found that TLR2, but not TLR4, could confer responsiveness to LAM isolated from rapidly growing mycobacteria. In contrast, LAM isolated from M. tuberculosis or Mycobacterium bovis bacillus Calmette-Guérin failed to induce TLR-dependent activation. Lastly, both soluble and cell wall-associated mycobacterial factors were capable of mediating activation via distinct TLR proteins. A soluble heat-stable and protease-resistant factor was found to mediate TLR2-dependent activation, whereas a heat-sensitive cell-associated mycobacterial factor mediated TLR4-dependent activation. Together, our data demonstrate that Toll-like receptors can mediate cellular activation by M. tuberculosis via CD14-independent ligands that are distinct from the mycobacterial cell wall glycolipid LAM.

• Publication year

  1999

• Venue

  Journal of Immunology

• Publication date

  1999-10-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.4049/jimmunol.163.7.3920PMID 10490993
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2*

  1999cited by this paper
• TLR6: A novel member of an expanding toll-like receptor family.

  1999cited by this paper
• Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2.

  1999cited by this paper
• Use of a photoactivatable taxol analogue to identify unique cellular targets in murine macrophages: identification of murine CD18 as a major taxol-binding protein and a role for Mac-1 in taxol-induced gene expression.

  1999cited by this paper
• Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction*

  1999cited by this paper
• Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4)

  1999cited by this paper
• Macrophages and tuberculosis

  1998cited by this paper
• Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling

  1998cited by this paper
• Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide

  1998cited by this paper
• A family of human receptors structurally related to Drosophila Toll.

  1998cited by this paper
• Proteolytic processing of the Drosophila Spätzle protein by easter generates a dimeric NGF-like molecule with ventralising activity.

  1998cited by this paper
• Signal transduction pathways activated by the IL‐1 receptor family: ancient signaling machinery in mammals, insects, and plants

  1998cited by this paper
• LPS‐binding proteins and receptors

  1998cited by this paper
• Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.

  1998cited by this paper
• Getting knotted: a model for the structure and activation of Spätzle.

  1998cited by this paper
• Construction of a lipopolysaccharide reporter cell line and its use in identifying mutants defective in endotoxin, but not TNF-alpha, signal transduction.

  1998cited by this paper
• Innate Immunity: The Virtues of a Nonclonal System of Recognition

  1997cited by this paper
• The 18‐wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense

  1997cited by this paper
• A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

  1997cited by this paper
• Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice.

  1996cited by this paper
• The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults.

  1996cited by this paper
• Mycobacterial lipoarabinomannan recognition requires a receptor that shares components of the endotoxin signaling system.

  1996cited by this paper
• Selective receptor blockade during phagocytosis does not alter the survival and growth of Mycobacterium tuberculosis in human macrophages.

  1996cited by this paper
• Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components.

  1995cited by this paper
• CD14 receptor-mediated uptake of nonopsonized Mycobacterium tuberculosis by human microglia

  1995cited by this paper
• The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo.

  1994cited by this paper
• Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors.

  1993cited by this paper
• Structure and antigenicity of lipoarabinomannan from Mycobacterium bovis BCG.

  1993cited by this paper
• Mycobacteria-macrophage interactions. Macrophage phenotype determines the nonopsonic binding of Mycobacterium tuberculosis to murine macrophages.

  1993cited by this paper
• Macrophage activation: lipoarabinomannan from avirulent and virulent strains of Mycobacterium tuberculosis differentially induces the early genes c-fos, KC, JE, and tumor necrosis factor-alpha.

  1993cited by this paper
• Structural basis of capacity of lipoarabinomannan to induce secretion of tumor necrosis factor

  1992cited by this paper
• The functional importance of a cap site-proximal region of the human prointerleukin 1 beta gene is defined by viral protein trans-activation

  1992cited by this paper
• Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells.

  1989cited by this paper

• The lipid language of tuberculosis: Mycobacterium tuberculosis surface molecules in host interaction and drug resistance

  2026cites this paper
• Insights on natural products and their derivatives in tuberculosis management

  2025cites this paper
• "The cytokine profiles of the inflammatory response in chronic granulomatous encephalitis caused by Mycobacterium tuberculosis do not influence the patient's clinical presentation".

  2025cites this paper
• Role of Transcription Factor NR1H3 in the Pathogenesis of Tuberculosis

  2025cites this paper
• Early secretory antigen target of 6-kDa of Mycobacterium tuberculosis inhibits macrophage apoptosis and host defense via TLR2

  2025cites this paper
• PBMC and fibroblast cocultures to mimic the in vivo effect of BCG on trained immunity

  2025cites this paper
• PPARdelta: A key modulator in the pathogenesis of diabetes mellitus and Mycobacterium tuberculosis co-morbidity

  2024cites this paper
• Effective Production of Snake Antivenom by Targeting Epidermal Dendritic Cells via the 'Low Dose, Low Volume, Multi-site' Immunization.

  2024cites this paper
• The balance between antiviral and antibacterial responses during M. tuberculosis infection is regulated by the ubiquitin ligase CBL

  2024cites this paper
• ROLE OF HISTONE DEACETYLASES IN REGULATION OF MACROPHAGE PHAGOCYTOSIS OF MYCOBACTERIUM TUBERCULOSIS

  2023cites this paper
• Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques.

  2023cites this paper
• Polymorphism of Toll-like Receptor 4 is Correlated with an Increased Risk of Mortality of Hemodialysis Patients: A Retrospective Cohort Study in Taiwanese

  2023cites this paper
• The cause–effect relation of tuberculosis on incidence of diabetes mellitus

  2023influential citation
• Pathogenicity of Type I Interferons in Mycobacterium tuberculosis

  2023cites this paper
• Immunomodulatory properties of morphine and the hypothesised role of long-term opioid use in the immunopathogenesis of tuberculosis

  2023cites this paper
• The molecular basis and downstream immune consequences of mycobacteria-host cell interactions.

  2023cites this paper
• Vitamin D and estrogen steroid hormones and their immunogenetic roles in Infectious respiratory (TB and COVID-19) diseases

  2023influential citation
• Curing Functions and Medical Applications of Microalgae

  2023cites this paper
• Immunogenicity of snake α-neurotoxins and the CD4 T cell epitopes.

  2022cites this paper
• Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis

  2022cites this paper
• Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

  2022cites this paper
• Pulmonary tuberculosis susceptibility and association with Toll-Like receptor 2 Arg753Gln polymorphism.

  2022cites this paper
• Stromal structure remodeling by B lymphocytes limits T cell activation in lymph nodes of Mycobacterium tuberculosis–infected mice

  2022cites this paper
• Recent Advances in the Development of Toll-like Receptor Agonist-Based Vaccine Adjuvants for Infectious Diseases

  2022cites this paper
• Systemic prime exacerbates the ocular immune response to heat-killed Mycobacterium tuberculosis

  2022cites this paper
• An Overview of Color Transfer and Style Transfer for Images and Videos

  2022influential citation
• Distinct contributions of the innate immune receptors TLR2 and RP105 to formation and architecture of structured lung granulomas in mice infected with Mycobacterium tuberculosis

  2022cites this paper
• Lipid mediated inhibition of Niemann-Pick C1 protein is an evolutionary conserved feature of multiple Mycobacterium lineages and non-tubercular mycobacteria

  2021cites this paper
• Innate Immune Pattern Recognition Receptors of Mycobacterium tuberculosis: Nature and Consequences for Pathogenesis of Tuberculosis.

  2021cites this paper
• References

  2021cites this paper
• Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

  2021influential citation
• Mycobacterium tuberculosis RipA Dampens TLR4-Mediated Host Protective Response Using a Multi-Pronged Approach Involving Autophagy, Apoptosis, Metabolic Repurposing, and Immune Modulation

  2021influential citation
• Cholesterol metabolism: from lipidomics to immunology

  2021cites this paper
• Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival

  2021cites this paper
• A Quest for a Universal Plasma-Derived Antivenom Against All Elapid Neurotoxic Snake Venoms

  2021cites this paper
• Generation of Liposomes to Study the Effect of Mycobacterium Tuberculosis Lipids on HIV-1 cis- and trans-Infections

  2021cites this paper
• Licensed Bacille Calmette-Guérin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation

  2020cites this paper
• C-type Lectins in Immunity to Lung Pathogens.

  2020cites this paper
• Single Nucleotide Polymorphisms in TLR4 Affect Susceptibility to Tuberculosis in Mexican Population from the State of Veracruz

  2020cites this paper
• Nicotine modulates molecules of the innate immune response in epithelial cells and macrophages during infection with M. tuberculosis

  2020cites this paper
• Toll-like receptor 2 polymorphisms and their effect on the immune response to ESAT-6, Pam3CSK4 TLR2 agonist in pulmonary tuberculosis patients and household contacts.

  2020cites this paper
• Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

  2020cites this paper
• Detection of non-endotoxin pyrogens by Monocyte Activation Test (MAT) using the PyroMAT® system

  2020cites this paper
• Sequence-Based Structural and Evolution of Polymorphisms in Bovine Toll-Like Receptor2 Gene in Dhanni and Jersey Cattle Breeds. Genetic polymorphisms in bovine TLR2

  2020cites this paper
• Mechanism of 1,25(OH)2D3 in the Treatment of Acute Lung Injury Based on UHPLC/Q-TOF MS-Based Metabolomics and Network Pharmacology

  2020cites this paper
• Cholesterol metabolism pathways – are the intermediates more important than the products?

  2020cites this paper
• Application of antigenic biomarkers for Mycobacterium tuberculosis

  2020cites this paper
• Orang dengan Latent Tuberculosis Infection

  2020cites this paper
• Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells.

  2020cites this paper
• PGRS Domain of Rv0297 of Mycobacterium tuberculosis Is Involved in Modulation of Macrophage Functions to Favor Bacterial Persistence

  2020cites this paper
• An overview of insect innate immunity

  2020cites this paper
• Immunostimulatory Activities of CpG-Oligodeoxynucleotides in Teleosts: Toll-Like Receptors 9 and 21

  2019cites this paper
• Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children

  2019cites this paper
• DNA from virulent M. tuberculosis induces TNF-α production and autophagy in M1 polarized macrophages.

  2019cites this paper
• Impact of Emotional Intelligence on Pastors’ Leadership Effectiveness in Churches of Southwest, Nigeria

  2019cites this paper
• Nanomedicines as Drug Delivery Carriers of Anti-Tubercular Drugs: From Pathogenesis to Infection Control

  2019cites this paper
• Polymorphisms in the P2X7 receptor, and differential expression of Toll-like receptor-mediated cytokines and defensins, in a Canadian Indigenous group

  2019cites this paper
• Cutaneous Tuberculosis

  2019cites this paper
• Genetic Variability and Its Vulnerability in Tuberculosis Infection

  2018cites this paper
• Tuberculosis: Smart manipulation of a lethal host

  2018cites this paper
• Comparative proteomics identified immune response proteins involved in response to vaccination with heat-inactivated Mycobacterium bovis and mycobacterial challenge in cattle.

  2018cites this paper
• The immunopathogenesis of chronic and relapsing autoimmune uveitis – Lessons from experimental rat models

  2018cites this paper
• Evaluation of anti-tuberculosis potentials of selected medicinal plants in Endau Rompin, Johor, Malaysia

  2018cites this paper
• Association of Toll like receptor 2 and 9 gene variants with pulmonary tuberculosis: exploration in a northern Indian population

  2018cites this paper
• Computationally Designed Bispecific MD2/CD14 Binding Peptides Show TLR4 Agonist Activity

  2018cites this paper
• Mathematical and computational approaches in understanding the immunobiology of granulomatous diseases

  2018cites this paper
• Mycobacterium tuberculosis Lipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes

  2018cites this paper
• Mycobacterium tuberculosis GrpE, A Heat-Shock Stress Responsive Chaperone, Promotes Th1-Biased T Cell Immune Response via TLR4-Mediated Activation of Dendritic Cells

  2018cites this paper
• The C-Type Lectin Receptor DC-SIGN Has an Anti-Inflammatory Role in Human M(IL-4) Macrophages in Response to Mycobacterium tuberculosis

  2018cites this paper
• System-wide coordinates of higher order functions in host-pathogen environment upon Mycobacterium tuberculosis infection

  2018cites this paper
• Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling.

  2018influential citation
• CD14 gene polymorphisms associated with increased risk of bovine tuberculosis in Chinese Holstein cows.

  2018cites this paper
• The Relationship Between Toll-Like Receptor 2 Mutation And IL-1 Receptor Antagonist Polymorphism With Tuberculosis Disease

  2018cites this paper
• Significance of CCL2 (−2518A/G), CCR2 (190G/A) and TLR4 polymorphisms (896 A/G and 1196C/T) in tuberculosis risk in Indian population

  2018cites this paper
• Generalized Correntropy based deep learning in presence of non-Gaussian noises

  2018cites this paper
• The N‐terminal peptide moiety of the Mycobacterium tuberculosis 19 kDa lipoprotein harbors RP105‐agonistic properties

  2018cites this paper
• Understanding the Role of Innate Immunity in the Response to Intracortical Microelectrodes.

  2018cites this paper
• Decreased microRNA-140-5p contributes to respiratory syncytial virus disease through targeting Toll-like receptor 4.

  2018cites this paper
• Cell envelope lipids in the pathophysiology of Mycobacterium tuberculosis.

  2018cites this paper
• Drug development against tuberculosis: Impact of alkaloids.

  2017cites this paper
• Diabetes Mellitus and Increased Tuberculosis Susceptibility : The Role of Short-Chain Fatty Acids Ekta

  2017cites this paper
• Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation

  2017cites this paper
• New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection

  2017cites this paper
• TLR‐4/miRNA‐32‐5p/FSTL1 signaling regulates mycobacterial survival and inflammatory responses in Mycobacterium tuberculosis‐infected macrophages

  2017cites this paper
• Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements

  2017cites this paper
• NOD 2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis 12 3 1 2 3 4

  2017cites this paper
• MiR‐23a‐5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF‐&kgr;B pathway by targeting TLR2

  2017cites this paper
• Tuberculosis in the elderly: Why inflammation matters

  2017cites this paper
• Tuberculosis of the Central Nervous System

  2017cites this paper
• Recognition of Mycobacterial Lipids by Immune Receptors.

  2017cites this paper
• TLR2 contributes to trigger immune response of pleural mesothelial cells against Mycobacterium bovis BCG and M. tuberculosis infection

  2017cites this paper
• Defining the boundaries of a healthy immune response using standardized immune monitoring tools

  2017cites this paper
• The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

  2017cites this paper
• Mycobacterium tuberculosis Interactions with Dendritic Cells and Macrophages

  2017cites this paper
• Pathogenesis of Tuberculosis of the Nervous System

  2017cites this paper
• Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells

  2017cites this paper
• Expression of Toll-like Receptor 2 and Toll-like Receptor 4 in Tuberculous Pleural Effusion.

  2017cites this paper
• Membrane vesicle trafficking of immune modulatory stimuli during Mycobacterium tuberculosis infection

  2017cites this paper
• Macrophage Infection by Mycobacteria

  2016influential citation
• Lipoarabinomannan, and its related glycolipids, induce divergent and opposing immune responses to Mycobacterium tuberculosis depending on structural diversity and experimental variations.

  2016cites this paper