Role of TLR1 and TLR6 in the host defense against disseminated candidiasis.

Toll-like receptor-1 (TLR1) and TLR6 are receptors of the TLR family that form heterodimers with TLR2. The role of TLR1 and TLR6 for the recognition of the fungal pathogen Candida albicans was investigated. TLR1 is not involved in the recognition of C. albicans, and TLR1 knock-out (TLR1-/-) mice showed a normal susceptibility to disseminated candidiasis. In contrast, recognition of C. albicans by TLR6 modulated the balance between Th1 and Th2 cytokines, and TLR6 knock-out mice displayed a defective production of IL-10 and an increased IFN-gamma release. Production of the monocyte-derived cytokines tumor necrosis factor, IL-1, and IL-6 was normal in TLR6-/- mice, and this was accompanied by a normal susceptibility to disseminated candidiasis. In conclusion, TLR6 is involved in the recognition of C. albicans and modulates the Th1/Th2 cytokine balance, but this results in a mild phenotype with a normal susceptibility of TLR6-/- mice to Candida infection.

[1]  B. Pulendran,et al.  Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. , 2006, The Journal of clinical investigation.

[2]  S. Akira,et al.  Discrimination of bacterial lipoproteins by Toll-like receptor 6. , 2001, International immunology.

[3]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. Netea,et al.  Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells , 2004, The Journal of Immunology.

[5]  Claire Collins,et al.  Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. , 2006, The Journal of clinical investigation.

[6]  M. Netea,et al.  Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. , 1996, The Journal of clinical investigation.

[7]  J. O'connor,et al.  Toll-like receptor-2 is essential in murine defenses against Candida albicans infections. , 2004, Microbes and infection.

[8]  J. O'connor,et al.  Myeloid differentiation factor 88 (MyD88) is required for murine resistance to Candida albicans and is critically involved in Candida -induced production of cytokines. , 2004, European cytokine network.

[9]  T. Klein,et al.  Involvement of mannose receptor in cytokine interleukin-1beta (IL-1beta), IL-6, and granulocyte-macrophage colony-stimulating factor responses, but not in chemokine macrophage inflammatory protein 1beta (MIP-1beta), MIP-2, and KC responses, caused by attachment of Candida albicans to macrophages , 1997, Infection and immunity.

[10]  R. Coffman,et al.  Interleukin‐4 and ‐10 exacerbate candidiasis in mice , 1995, European journal of immunology.

[11]  S. Akira,et al.  Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins1 , 2002, The Journal of Immunology.

[12]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[13]  R. Lehrer,et al.  Interaction of Candida albicans with Human Leukocytes and Serum , 1969, Journal of bacteriology.

[14]  M. Netea,et al.  Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans. , 1999, Journal of immunology.

[15]  M. Netea,et al.  The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. , 2002, The Journal of infectious diseases.

[16]  B. Kullberg,et al.  Role of granulocytes in increased host resistance to Candida albicans induced by recombinant interleukin-1 , 1990, Infection and immunity.

[17]  R. Wenzel,et al.  Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  K. Triantafilou,et al.  Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. , 2002, Trends in immunology.

[19]  Linda N. Lee,et al.  Secretion of Proinflammatory Cytokines and Chemokines during Amphotericin B Exposure Is Mediated by Coactivation of Toll-Like Receptors 1 and 2 , 2005, Antimicrobial Agents and Chemotherapy.

[20]  S. Gordon,et al.  Characteristics of Invasive Candidiasis in Gamma Interferon- and Interleukin-4-Deficient Mice: Role of Macrophages in Host Defense against Candida albicans , 1998, Infection and Immunity.

[21]  T. Hartung,et al.  Membrane Sorting of Toll-like Receptor (TLR)-2/6 and TLR2/1 Heterodimers at the Cell Surface Determines Heterotypic Associations with CD36 and Intracellular Targeting* , 2006, Journal of Biological Chemistry.

[22]  Shizuo Akira,et al.  Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2 , 2003, The Journal of experimental medicine.

[23]  S. Gordon,et al.  Dectin-1 is required for β-glucan recognition and control of fungal infection , 2007, Nature Immunology.

[24]  S. Melnick,et al.  Mechanism of macrophage activation by (1,4)-α-d-glucan isolated from Tinospora cordifolia , 2006 .

[25]  Siamon Gordon,et al.  Dectin-1 Is A Major β-Glucan Receptor On Macrophages , 2002, The Journal of experimental medicine.

[26]  B. Kullberg,et al.  Recombinant interferon-gamma enhances resistance to acute disseminated Candida albicans infection in mice. , 1993, The Journal of infectious diseases.

[27]  Shane Gillespie,et al.  Attributable mortality of nosocomial candidemia, revisited. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[28]  M. Chamaillard,et al.  Specific Recognition of Candida albicans by Macrophages Requires Galectin-3 to Discriminate Saccharomyces cerevisiae and Needs Association with TLR2 for Signaling1 , 2006, The Journal of Immunology.

[29]  A. Mantovani,et al.  The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo1 , 2004, The Journal of Immunology.

[30]  Osamu Takeuchi,et al.  Candida albicans phospholipomannan is sensed through toll-like receptors. , 2003, The Journal of infectious diseases.

[31]  E. Nemoto,et al.  Saccharomyces cerevisiae‐ and Candida albicans‐Derived Mannan Induced Production of Tumor Necrosis Factor Alpha by Human Monocytes in a CD14‐ and Toll‐Like Receptor 4‐Dependent Manner , 2002, Microbiology and immunology.

[32]  C. Hughes,et al.  Of Mice and Not Men: Differences between Mouse and Human Immunology , 2004, The Journal of Immunology.

[33]  J. Satagopan,et al.  TLR1 and TLR6 Polymorphisms Are Associated with Susceptibility to Invasive Aspergillosis after Allogeneic Stem Cell Transplantation , 2005, Annals of the New York Academy of Sciences.