Innate immunity in tuberculosis: myths and truth.

Tuberculosis is the most important bacterial infection world wide. The causative agent, Mycobacterium tuberculosis survives and proliferates within macrophages. Immune mediators such as interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) activate macrophages and promote bacterial killing. IFN-gamma is predominantly secreted by innate cells (mainly natural killer (NK) cells) and by T cells upon instruction by interleukin 12 (IL-12) and IL-18. These cytokines are primarily produced by dendritic cells and macrophages in response to Toll-like receptor (TLR) signalling interaction with tubercle bacilli. These signals also induce pro-inflammatory cytokines (including IL-1beta and TNF-alpha), chemokines and defensins. The inflammatory environment further recruits innate effector cells such as macrophages, polymorphonuclear neutrophils (PMN) and NK cells to the infectious foci. This eventually leads to the downstream establishment of acquired T cell immunity which appears to be protective in more than 90% of infected individuals. Robust innate immune activation is considered an essential prerequisite for protective immunity and vaccine efficacy. However, data published so far provide a muddled view of the functional importance of innate immunity in tuberculosis. Here we critically discuss certain aspects of innate immunity, namely PMN, TLRs and NK cells, as characterised in tuberculosis to date, and their contribution to protection and pathology.

[1]  R. Appelberg.  Mycobacterial Infection Primes T Cells and Macrophages for Enhanced Recruitment of Neutrophils , 1992, Journal of leukocyte biology.

[2]  In-Jeong Kim,et al.  Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFN gamma-inducible fibrinogen-like protein 2. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Ryffel,et al.  Toll-Like Receptor 4 Expression Is Required to Control Chronic Mycobacterium tuberculosis Infection in Mice1 , 2002, The Journal of Immunology.

[4]  S. Santiwatanakul,et al.  Cytokine production in NK and NKT cells from Mycobacterium tuberculosis infected patients. , 2007, The Southeast Asian journal of tropical medicine and public health.

[5]  W. Rom,et al.  The host immune response to tuberculosis. , 1998, American journal of respiratory and critical care medicine.

[6]  S. Akira,et al.  Containment of aerogenic Mycobacterium tuberculosis infection in mice does not require MyD88 adaptor function for TLR2, ‐4 and ‐9 , 2008, European journal of immunology.

[7]  L. Lanier,et al.  Natural killer cells as an initial defense against pathogens , 2006, Current Opinion in Immunology.

[8]  Giorgio Sirugo,et al.  A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis , 2007, Nature Genetics.

[9]  M. Kelliher,et al.  NOD2 Pathway Activation by MDP or Mycobacterium tuberculosis Infection Involves the Stable Polyubiquitination of Rip2* , 2007, Journal of Biological Chemistry.

[10]  J. Harty,et al.  Neutrophil Involvement in Cross-Priming CD8+ T Cell Responses to Bacterial Antigens1 , 2004, The Journal of Immunology.

[11]  N. Reiling,et al.  MyDths and un-TOLLed truths: sensor, instructive and effector immunity to tuberculosis. , 2008, Immunology letters.

[12]  P. Schierloh,et al.  Spontaneous or Mycobacterium tuberculosis‐induced apoptotic neutrophils exert opposite effects on the dendritic cell‐mediated immune response , 2007, European journal of immunology.

[13]  P. Schierloh,et al.  NK cell activity in tuberculosis is associated with impaired CD11a and ICAM‐1 expression: a regulatory role of monocytes in NK activation , 2005, Immunology.

[14]  N. Connell,et al.  Natural killer cells, glutathione, cytokines, and innate immunity against Mycobacterium tuberculosis. , 2008, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[15]  W. Britton,et al.  Life and death in the granuloma: immunopathology of tuberculosis , 2007, Immunology and cell biology.

[16]  M. Yadav,et al.  The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. , 2006, Blood.

[17]  P. Spagnuolo,et al.  Evidence for activation of a respiratory burst in the interaction of human neutrophils with Mycobacterium tuberculosis , 1987, Infection and immunity.

[18]  A. Segal,et al.  How neutrophils kill microbes. , 2005, Annual review of immunology.

[19]  M. Denis.  Interleukin-12 (IL-12) augments cytolytic activity of natural killer cells toward Mycobacterium tuberculosis-infected human monocytes. , 1994, Cellular immunology.

[20]  S. Ress,et al.  Reduced NK activity correlates with active disease in HIV patients with multidrug‐resistant pulmonary tuberculosis , 1994, Clinical and experimental immunology.

[21]  S. Kaufmann,et al.  Chemokine secretion by human polymorphonuclear granulocytes after stimulation with Mycobacterium tuberculosis and lipoarabinomannan , 1997, Infection and immunity.

[22]  D. Kaplan,et al.  Human Natural Killer Cells Mediate Killing of Intracellular Mycobacterium tuberculosis H37Rv via Granule-Independent Mechanisms , 2001, Infection and Immunity.

[23]  A. Sher,et al.  MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression , 2004, Infection and Immunity.

[24]  P. Schierloh,et al.  Mycobacterium tuberculosis-Induced Gamma Interferon Production by Natural Killer Cells Requires Cross Talk with Antigen-Presenting Cells Involving Toll-Like Receptors 2 and 4 and the Mannose Receptor in Tuberculous Pleurisy , 2007, Infection and Immunity.

[25]  P. Schierloh,et al.  Increased Susceptibility to Apoptosis of CD56dimCD16+ NK Cells Induces the Enrichment of IFN-γ-Producing CD56bright Cells in Tuberculous Pleurisy1 , 2005, The Journal of Immunology.

[26]  R. Wilkinson,et al.  Neutrophil-mediated innate immune resistance to mycobacteria. , 2007, The Journal of clinical investigation.

[27]  A. Krensky,et al.  Granulysin: a lethal weapon of cytolytic T cells. , 1999, Immunology today.

[28]  Michael D. Liang,et al.  TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG , 2003, Journal of leukocyte biology.

[29]  H. Heine,et al.  TLR2 - promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. , 2008, Immunobiology.

[30]  I. Orme,et al.  NK Cells Respond to Pulmonary Infection with Mycobacterium tuberculosis, but Play a Minimal Role in Protection 1 , 2003, The Journal of Immunology.

[31]  J. Ernst,et al.  Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosis in human neutrophils. , 1998, Microbial pathogenesis.

[32]  R. Locksley,et al.  IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge , 2007, Nature Immunology.

[33]  W. Nauseef.  How human neutrophils kill and degrade microbes: an integrated view , 2007, Immunological reviews.

[34]  P. Schierloh,et al.  In tuberculous pleural effusions, activated neutrophils undergo apoptosis and acquire a dendritic cell-like phenotype. , 2005, The Journal of infectious diseases.

[35]  M. Sasiain,et al.  Mycobacterium tuberculosis-induced activation accelerates apoptosis in peripheral blood neutrophils from patients with active tuberculosis. , 2002, American journal of respiratory cell and molecular biology.

[36]  W. Rom,et al.  Local immune responses correlate with presentation and outcome in tuberculosis. , 1998, American journal of respiratory and critical care medicine.

[37]  Michael D. Connolly,et al.  Use of Ly6G‐specific monoclonal antibody to deplete neutrophils in mice , 2008, Journal of leukocyte biology.

[38]  V. Deretic,et al.  Toll‐like receptors control autophagy , 2008, The EMBO journal.

[39]  S. Kaufmann,et al.  Rapid neutrophil response controls fast-replicating intracellular bacteria but not slow-replicating Mycobacterium tuberculosis. , 2000, The Journal of infectious diseases.

[40]  P. E. M. Fine,et al.  Variation in protection by BCG: implications of and for heterologous immunity , 1995, The Lancet.

[41]  K. Kisich,et al.  Tumor Necrosis Factor Alpha Stimulates Killing of Mycobacterium tuberculosis by Human Neutrophils , 2002, Infection and Immunity.

[42]  Sugata Roy,et al.  NK Cells Lyse T Regulatory Cells That Expand in Response to an Intracellular Pathogen1 , 2008, The Journal of Immunology.

[43]  A. Stringaro,et al.  Direct Binding of Human NK Cell Natural Cytotoxicity Receptor NKp44 to the Surfaces of Mycobacteria and Other Bacteria , 2008, Infection and Immunity.

[44]  J. Farrar,et al.  A common human TLR1 polymorphism regulates the innate immune response to lipopeptides , 2007, European journal of immunology.

[45]  I. McInnes,et al.  IL‐18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background , 2000, European journal of immunology.

[46]  V. Deretic,et al.  Human IRGM Induces Autophagy to Eliminate Intracellular Mycobacteria , 2006, Science.

[47]  T. Ganz,et al.  Macrophages Acquire Neutrophil Granules for Antimicrobial Activity against Intracellular Pathogens1 , 2006, The Journal of Immunology.

[48]  L. Moretta,et al.  NK cells at the interface between innate and adaptive immunity , 2008, Cell Death and Differentiation.

[49]  V. Deretic,et al.  Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages , 2004, Cell.

[50]  T. Shim,et al.  Toll-like receptor 4 plays no role in susceptibility of mice to Mycobacterium tuberculosis infection. , 2003, Tuberculosis.

[51]  S. Kaufmann,et al.  Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide , 2008, Cellular microbiology.

[52]  S. Akira,et al.  Role of Interleukin-18 (IL-18) in Mycobacterial Infection in IL-18-Gene-Disrupted Mice , 1999, Infection and Immunity.

[53]  S. Akira,et al.  Mycobacterial Infection in TLR2 and TLR6 Knockout Mice , 2003, Microbiology and immunology.

[54]  T. van der Poll,et al.  Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. , 2000, The Journal of infectious diseases.

[55]  T. Ottenhoff,et al.  Not to wake a sleeping giant: new insights into host-pathogen interactions identify new targets for vaccination against latent Mycobacterium tuberculosis infection , 2008, Biological chemistry.

[56]  B. Ryffel,et al.  Innate immunity to mycobacterial infection in mice: critical role for toll-like receptors. , 2005, Tuberculosis.

[57]  S. Akira,et al.  Mycobacterial Infection in MyD88‐Deficient Mice , 2003, Microbiology and immunology.

[58]  D. Russell,et al.  TLR signalling and phagosome maturation: an alternative viewpoint , 2007, Cellular microbiology.

[59]  B. Andersen,et al.  Capacity of human neutrophils to kill Mycobacterium tuberculosis. , 1987, The Journal of infectious diseases.

[60]  I. Orme,et al.  Rapid Accumulation of Eosinophils in Lung Lesions in Guinea Pigs Infected with Mycobacterium tuberculosis , 2004, Infection and Immunity.

[61]  L. Quintana-Murci,et al.  Towards a crucial role for DC-SIGN in tuberculosis and beyond. , 2006, Trends in microbiology.

[62]  E. Riley,et al.  Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens , 2007, Nature Reviews Immunology.

[63]  R. Appelberg,et al.  Neutrophils Play a Protective Nonphagocytic Role in Systemic Mycobacterium tuberculosis Infection of Mice , 2000, Infection and Immunity.

[64]  R. North,et al.  Immunity to tuberculosis. , 2003, Annual review of immunology.

[65]  T. Mak,et al.  The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis 1 , 2005, The Journal of Immunology.

[66]  S. Khader,et al.  Interleukin-12 and tuberculosis: an old story revisited. , 2007, Current opinion in immunology.

[67]  H. Yamada,et al.  Rat Neutrophils Prevent the Development of Tuberculosis , 2004, Infection and Immunity.

[68]  O. Mandelboim,et al.  The NKp46 Receptor Contributes to NK Cell Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium1 , 2002, The Journal of Immunology.

[69]  H. Mollenkopf,et al.  Early granuloma formation after aerosol Mycobacterium tuberculosis infection is regulated by neutrophils via CXCR3‐signaling chemokines , 2003, European journal of immunology.

[70]  Y. Okubo,et al.  Analysis of immunologic mechanisms of high natural killer cell activity in tuberculous pleural effusions. , 1990, The American review of respiratory disease.

[71]  I. Sugawara,et al.  Interleukin-18 (IL-18) and infectious diseases, with special emphasis on diseases induced by intracellular pathogens. , 2000, Microbes and infection.

[72]  G. Trinchieri,et al.  Reciprocal Activating Interaction between Natural Killer Cells and Dendritic Cells , 2002, The Journal of experimental medicine.

[73]  B. Ryffel,et al.  Toll-like receptor pathways in the immune responses to mycobacteria. , 2004, Microbes and infection.

[74]  L. Tailleux,et al.  How is the phagocyte lectin keyboard played? Master class lesson by Mycobacterium tuberculosis. , 2003, Trends in microbiology.

[75]  Y. Iwakura,et al.  Protective Role of Interleukin-1 in Mycobacterial Infection in IL-1 α/β Double-Knockout Mice , 2000, Laboratory Investigation.

[76]  B. Ryffel,et al.  Toll-like receptor 2-deficient mice succumb to Mycobacterium tuberculosis infection. , 2004, The American journal of pathology.

[77]  N. Reiling,et al.  Cutting Edge: Toll-Like Receptor (TLR)2- and TLR4-Mediated Pathogen Recognition in Resistance to Airborne Infection with Mycobacterium tuberculosis1 , 2002, The Journal of Immunology.

[78]  M. Adachi,et al.  Expression of chemokines and induction of rapid cell death in human blood neutrophils by Mycobacterium tuberculosis. , 1998, The Journal of infectious diseases.

[79]  S. Khader,et al.  IL-23 and IL-17 in tuberculosis. , 2008, Cytokine.

[80]  M. Netea,et al.  NOD2 and Toll-Like Receptors Are Nonredundant Recognition Systems of Mycobacterium tuberculosis , 2005, PLoS pathogens.

[81]  M. Sweet,et al.  Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice. , 1999, Journal of immunology.

[82]  J. Chiche,et al.  The importance of Toll-like receptor 2 polymorphisms in severe infections. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[83]  A. Sher,et al.  TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis , 2005, The Journal of experimental medicine.

[84]  R. Medzhitov,et al.  Regulation of Phagosome Maturation by Signals from Toll-Like Receptors , 2004, Science.

[85]  B. Ryffel,et al.  IL-1 Receptor-Mediated Signal Is an Essential Component of MyD88-Dependent Innate Response to Mycobacterium tuberculosis Infection , 2007, The Journal of Immunology.

[86]  E. Coccia,et al.  IFN-αβ Released by Mycobacterium tuberculosis-Infected Human Dendritic Cells Induces the Expression of CXCL10: Selective Recruitment of NK and Activated T Cells 1 , 2003, The Journal of Immunology.

[87]  A. Porgador,et al.  Role of NK Cell-Activating Receptors and Their Ligands in the Lysis of Mononuclear Phagocytes Infected with an Intracellular Bacterium1 , 2005, The Journal of Immunology.

[88]  R. Appelberg,et al.  Neutrophils and intracellular pathogens: beyond phagocytosis and killing. , 2007, Trends in microbiology.

[89]  J. Cutler,et al.  Assessment of a mouse model of neutropenia and the effect of an anti-candidiasis monoclonal antibody in these animals. , 1997, The Journal of infectious diseases.

[90]  D. Russell,et al.  Phagosome maturation proceeds independently of stimulation of toll-like receptors 2 and 4. , 2005, Immunity.

[91]  M. Isturiz,et al.  Activation of peripheral blood neutrophils from patients with active advanced tuberculosis. , 2001, Clinical immunology.

[92]  D. Green,et al.  Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis , 2007, Nature.

[93]  A. Apt,et al.  Neutrophil Responses to Mycobacterium tuberculosis Infection in Genetically Susceptible and Resistant Mice , 2005, Infection and Immunity.

[94]  A. Sher,et al.  NK Cell-Derived IFN-γ Differentially Regulates Innate Resistance and Neutrophil Response in T Cell-Deficient Hosts Infected with Mycobacterium tuberculosis , 2006, The Journal of Immunology.

[95]  N. Rawal,et al.  Vimentin Expressed on Mycobacterium tuberculosis-Infected Human Monocytes Is Involved in Binding to the NKp46 Receptor1 , 2006, The Journal of Immunology.

[96]  S. Akira,et al.  Genetically Resistant Mice Lacking IL-18 Gene Develop Th1 Response and Control Cutaneous Leishmania major Infection1 , 2000, The Journal of Immunology.