The role of the innate immune system on pulmonary infections

Abstract Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.

[1]  C. Zeiss,et al.  Surfactant protein C dampens inflammation by decreasing JAK/STAT activation during lung repair. , 2018, American journal of physiology. Lung cellular and molecular physiology.

[2]  Hilal Bashir,et al.  Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis , 2018, Front. Immunol..

[3]  A. Diefenbach,et al.  Group 1 innate lymphoid cells in Toxoplasma gondii infection , 2018, Parasite immunology.

[4]  R. Dziarski,et al.  How innate immunity proteins kill bacteria and why they are not prone to resistance , 2018, Current Genetics.

[5]  Merle L. Gilbert,et al.  Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges , 2018, mBio.

[6]  Brenton L. Scott,et al.  Combined aerosolized Toll‐like receptor ligands are an effective therapeutic agent against influenza pneumonia when co‐administered with oseltamivir , 2018, European journal of pharmacology.

[7]  John D Lambris,et al.  Factor H–IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes , 2017, The Journal of Immunology.

[8]  E. Lillehoj,et al.  MUC1: The First Respiratory Mucin with an Anti-Inflammatory Function , 2017, Journal of clinical medicine.

[9]  F. Ebner,et al.  Natural killer cell-intrinsic type I IFN signaling controls Klebsiella pneumoniae growth during lung infection , 2017, PLoS pathogens.

[10]  E. Lillehoj,et al.  Pseudomonas aeruginosa increases MUC1 expression in macrophages through the TLR4-p38 pathway. , 2017, Biochemical and biophysical research communications.

[11]  C. Akdis,et al.  Respiratory syncytial virus infection influences tight junction integrity , 2017, Clinical and experimental immunology.

[12]  F. Vély,et al.  Innate lymphoid cells: major players in inflammatory diseases , 2017, Nature Reviews Immunology.

[13]  Heejun Choi,et al.  Oxidative stress induced in E. coli by the human antimicrobial peptide LL-37 , 2017, PLoS pathogens.

[14]  D. Metzger,et al.  IFN-γ increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells , 2017, Mucosal Immunology.

[15]  F. Cecconi,et al.  Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance , 2017, Scientific Reports.

[16]  C. Steele,et al.  Innate Lung Defense during Invasive Aspergillosis: New Mechanisms , 2017, Journal of Innate Immunity.

[17]  T. Billiar,et al.  TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury , 2017, Scientific Reports.

[18]  H. Deshmukh,et al.  Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection , 2017, Science Translational Medicine.

[19]  C. Richards Innate Immune Cytokines, Fibroblast Phenotypes, and Regulation of Extracellular Matrix in Lung. , 2017, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[20]  S. Cormier,et al.  A Neonatal Murine Model of MRSA Pneumonia , 2017, PloS one.

[21]  O. Wittekindt Tight junctions in pulmonary epithelia during lung inflammation , 2016, Pflügers Archiv - European Journal of Physiology.

[22]  Janet S. Lee,et al.  IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae. , 2016, Cell host & microbe.

[23]  Hergen Spits,et al.  Human innate lymphoid cells. , 2016, The Journal of allergy and clinical immunology.

[24]  D. Artis,et al.  Emerging concepts and future challenges in innate lymphoid cell biology , 2016, The Journal of experimental medicine.

[25]  T. Mayadas,et al.  PKC‐δ activation in neutrophils promotes fungal clearance , 2016, Journal of leukocyte biology.

[26]  J. Kolls,et al.  Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia , 2016, The Journal of Immunology.

[27]  C. Johansson,et al.  Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons , 2016, Journal of Innate Immunity.

[28]  T. Randall,et al.  Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung , 2016, Front. Immunol..

[29]  C. Spencer,et al.  A Subset of Protective γ9δ2 T Cells Is Activated by Novel Mycobacterial Glycolipid Components , 2016, Infection and Immunity.

[30]  A. Gudkov,et al.  Powerful Complex Immunoadjuvant Based on Synergistic Effect of Combined TLR4 and NOD2 Activation Significantly Enhances Magnitude of Humoral and Cellular Adaptive Immune Responses , 2016, PloS one.

[31]  D. Andersson,et al.  Mechanisms and consequences of bacterial resistance to antimicrobial peptides. , 2016, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[32]  R. Bowler,et al.  Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs , 2016, Nature Immunology.

[33]  S. Ram,et al.  Defining the Binding Region in Factor H to Develop a Therapeutic Factor H-Fc Fusion Protein against Non-Typeable Haemophilus influenzae , 2016, Front. Cell. Infect. Microbiol..

[34]  M. Mann,et al.  Inflammatory signaling in human Tuberculosis granulomas is spatially organized , 2016, Nature Medicine.

[35]  Christine E. Becker,et al.  Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions , 2016, European Respiratory Journal.

[36]  G. Joos,et al.  Characterization and Quantification of Innate Lymphoid Cell Subsets in Human Lung , 2016, PloS one.

[37]  P. Hiemstra Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface. , 2015, Molecular immunology.

[38]  C. A. Fossati,et al.  CCL20 and Beta-Defensin 2 Production by Human Lung Epithelial Cells and Macrophages in Response to Brucella abortus Infection , 2015, PloS one.

[39]  Loreto Egaña,et al.  Alveolar macrophages support interferon gamma-mediated viral clearance in RSV-infected neonatal mice , 2015, Respiratory Research.

[40]  C. Romagnani,et al.  ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice , 2015, European journal of immunology.

[41]  L. Moretta,et al.  NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures , 2015, Nature Communications.

[42]  Y. Baglaenko,et al.  Pulmonary Chlamydia muridarum challenge activates lung interstitial macrophages which correlate with IFN‐γ production and infection control in mice , 2015, European journal of immunology.

[43]  M. Kuroda,et al.  Differentiation Kinetics of Blood Monocytes and Dendritic Cells in Macaques: Insights to Understanding Human Myeloid Cell Development , 2015, The Journal of Immunology.

[44]  A. Sáenz,et al.  Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN , 2015, The Journal of Immunology.

[45]  K. Rajarathnam,et al.  Chemokine CXCL1-Mediated Neutrophil Trafficking in the Lung: Role of CXCR2 Activation , 2015, Journal of Innate Immunity.

[46]  D. Niño,et al.  Sustained expression of lipocalin-2 during polymicrobial sepsis , 2015, Innate immunity.

[47]  Haitao Guo,et al.  Inflammasomes: mechanism of action, role in disease, and therapeutics , 2015, Nature Medicine.

[48]  A. Caliendo,et al.  Healthy HIV-1-infected individuals on highly active antiretroviral therapy harbor HIV-1 in their alveolar macrophages. , 2015, AIDS research and human retroviruses.

[49]  Simeone Marino,et al.  Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization , 2015, PLoS pathogens.

[50]  S. Nobs,et al.  The development and function of lung-resident macrophages and dendritic cells , 2014, Nature Immunology.

[51]  F. Geissmann,et al.  Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors , 2014, Nature.

[52]  E. Oldfield,et al.  Resistance-resistant antibiotics. , 2014, Trends in pharmacological sciences.

[53]  R. Garofalo,et al.  Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. , 2014, American journal of respiratory cell and molecular biology.

[54]  C. Reed,et al.  Hospitalizations for Severe Lower Respiratory Tract Infections , 2014, Pediatrics.

[55]  G. Ogg,et al.  MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion , 2014, Immunity.

[56]  Thomas B. Clarke Early Innate Immunity to Bacterial Infection in the Lung Is Regulated Systemically by the Commensal Microbiota via Nod-Like Receptor Ligands , 2014, Infection and Immunity.

[57]  K. Puan,et al.  Metabolic Engineering of Salmonella Vaccine Bacteria To Boost Human Vγ2Vδ2 T Cell Immunity , 2014, The Journal of Immunology.

[58]  J. Kolls,et al.  Directing traffic: IL‐17 and IL‐22 coordinate pulmonary immune defense , 2014, Immunological reviews.

[59]  T. Ross,et al.  Massive mobilization of dendritic cells during influenza A virus subtype H5N1 infection of nonhuman primates. , 2014, The Journal of infectious diseases.

[60]  Young-In Kim,et al.  Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection , 2014, Journal of Virology.

[61]  Charles C. Kim,et al.  Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion , 2014, Nature Immunology.

[62]  A. Osterhaus,et al.  Recombinant porcine surfactant protein D inhibits influenza A virus replication ex vivo. , 2014, Virus research.

[63]  C. Hunter,et al.  The Aryl Hydrocarbon Receptor Promotes IL-10 Production by NK Cells , 2014, The Journal of Immunology.

[64]  T. Hohl,et al.  Inflammatory Monocytes Orchestrate Innate Antifungal Immunity in the Lung , 2014, PLoS pathogens.

[65]  S. Sieg,et al.  Human β defensin‐3 induces chemokines from monocytes and macrophages: diminished activity in cells from HIV‐infected persons , 2013, Immunology.

[66]  Sarah S. Wilson,et al.  Antiviral Mechanisms of Human Defensins , 2013, Journal of Molecular Biology.

[67]  Bernard Malissen,et al.  Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF , 2013, The Journal of experimental medicine.

[68]  A. Ray,et al.  Immunosuppressive MDSCs induced by TLR signaling during infection and role in resolution of inflammation , 2013, Front. Cell. Infect. Microbiol..

[69]  L. Boon,et al.  Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes. , 2013, The Journal of clinical investigation.

[70]  Shibo Jiang,et al.  Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection. , 2013, American journal of respiratory cell and molecular biology.

[71]  H. Jomaa,et al.  Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates , 2013, PLoS pathogens.

[72]  G. Kaplan,et al.  Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis , 2013, Proceedings of the National Academy of Sciences.

[73]  O. Soehnlein,et al.  CCR5 and FPR1 Mediate Neutrophil Recruitment in Endotoxin-Induced Lung Injury , 2013, Journal of Innate Immunity.

[74]  L. Cardell,et al.  Innate Immune Receptors in Human Airway Smooth Muscle Cells: Activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 Agonists , 2013, PloS one.

[75]  F. Bushman,et al.  Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria , 2013, Nature.

[76]  Timothy M. Williams,et al.  M2 macrophage polarisation is associated with alveolar formation during postnatal lung development , 2013, Respiratory Research.

[77]  Kevin J. McHugh,et al.  IL-22 is essential for lung epithelial repair following influenza infection. , 2013, American Journal of Pathology.

[78]  M. Kaplan,et al.  Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia , 2013, The Journal of experimental medicine.

[79]  K. Rasmussen,et al.  Lung Surfactant Protein D (SP-D) Response and Regulation During Acute and Chronic Lung Injury , 2013, Lung.

[80]  A. Mildner,et al.  Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. , 2013, Immunity.

[81]  R. Locksley,et al.  Innate lymphoid cells — a proposal for uniform nomenclature , 2013, Nature Reviews Immunology.

[82]  K. C. Kim Role of epithelial mucins during airway infection. , 2012, Pulmonary pharmacology & therapeutics.

[83]  S. van Drunen Littel-van den Hurk,et al.  The role of dendritic cells in innate and adaptive immunity to respiratory syncytial virus, and implications for vaccine development , 2012, Expert review of vaccines.

[84]  M. Unemo,et al.  A Novel Factor H–Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae , 2012, The Journal of Immunology.

[85]  N. Chiba,et al.  Plasmacytoid Dendritic Cells Play a Role for Effective Innate Immune Responses during Chlamydia pneumoniae Infection in Mice , 2012, PloS one.

[86]  M. Braun,et al.  Complement Factor C7 Contributes to Lung Immunopathology Caused by Mycobacterium tuberculosis , 2012, Clinical & developmental immunology.

[87]  W. Ouyang,et al.  IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection , 2012, Mucosal Immunology.

[88]  F. D’Acquisto,et al.  Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo , 2012, The Journal of experimental medicine.

[89]  V. Nizet,et al.  Dual Dehydrosqualene/Squalene Synthase Inhibitors: Leads for Innate Immune System‐Based Therapeutics , 2012, ChemMedChem.

[90]  J. Dorin,et al.  β-Defensins: Multifunctional Modulators of Infection, Inflammation and More? , 2012, Journal of Innate Immunity.

[91]  K. Fitzgerald,et al.  Regulation of inflammasome signaling , 2012, Nature Immunology.

[92]  Yoko Ito,et al.  Innate Immune Response of Human Alveolar Macrophages during Influenza A Infection , 2012, PloS one.

[93]  N. Suttorp,et al.  Streptococcus pneumoniae induces human β-defensin-2 and -3 in human lung epithelium , 2012, Experimental lung research.

[94]  Mark A. Miller,et al.  Inflammasome-dependent Pyroptosis and IL-18 Protect against Burkholderia pseudomallei Lung Infection while IL-1β Is Deleterious , 2011, PLoS pathogens.

[95]  David Artis,et al.  Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus , 2011, Nature Immunology.

[96]  D. Riches,et al.  Lung dendritic cells at the innate‐adaptive immune interface , 2011, Journal of leukocyte biology.

[97]  B. Becher,et al.  IL-22 Is Produced by Innate Lymphoid Cells and Limits Inflammation in Allergic Airway Disease , 2011, PloS one.

[98]  J. Kolls,et al.  The development of inducible Bronchus Associated Lymphoid Tissue (iBALT) is dependent on IL-17 , 2011, Nature Immunology.

[99]  Y. Park,et al.  TNF-α is a key regulator of MUC1, an anti-inflammatory molecule, during airway Pseudomonas aeruginosa infection. , 2011, American journal of respiratory cell and molecular biology.

[100]  J. Fahy,et al.  Airway mucus function and dysfunction. , 2010, The New England journal of medicine.

[101]  V. Nizet,et al.  Statins enhance formation of phagocyte extracellular traps. , 2010, Cell host & microbe.

[102]  D. Dinwiddie,et al.  Anti-inflammatory effect of MUC1 during respiratory syncytial virus infection of lung epithelial cells in vitro. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[103]  Y. Suezer,et al.  Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells , 2009, The Journal of experimental medicine.

[104]  R. Schmid,et al.  Myeloid RelA regulates pulmonary host defense networks , 2009, European Respiratory Journal.

[105]  V. Nizet,et al.  A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence , 2008, Science.

[106]  M. Fei,et al.  IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia , 2008, Nature Medicine.

[107]  M. McGuckin,et al.  Structure and function of the polymeric mucins in airways mucus. , 2008, Annual review of physiology.

[108]  Kim L Kusser,et al.  Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza , 2007, Proceedings of the National Academy of Sciences.

[109]  M. Falagas,et al.  Effectiveness and nephrotoxicity of colistin monotherapy vs. colistin-meropenem combination therapy for multidrug-resistant Gram-negative bacterial infections. , 2006, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[110]  Kim L Kusser,et al.  Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. , 2006, Immunity.

[111]  Ayyalusamy Ramamoorthy,et al.  LL-37, the only human member of the cathelicidin family of antimicrobial peptides. , 2006, Biochimica et biophysica acta.

[112]  M. Rocchi,et al.  LL-37 Protects Rats against Lethal Sepsis Caused by Gram-Negative Bacteria , 2006, Antimicrobial Agents and Chemotherapy.

[113]  K. Rabe,et al.  The human cathelicidin LL-37: a multifunctional peptide involved in infection and inflammation in the lung. , 2005, Pulmonary pharmacology & therapeutics.

[114]  R. Hancock,et al.  Immunomodulatory Activities of Small Host Defense Peptides , 2005, Antimicrobial Agents and Chemotherapy.

[115]  R. Schleimer,et al.  Activation of airway epithelial cells by toll-like receptor agonists. , 2004, American journal of respiratory cell and molecular biology.

[116]  Kim L Kusser,et al.  Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity , 2004, Nature Medicine.

[117]  G. Belz,et al.  Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[118]  C. Smith,et al.  Unique structural features that influence neutrophil emigration into the lung. , 2003, Physiological reviews.

[119]  Ryan M. O’Connell,et al.  Toll-Like Receptor 3 Mediates a More Potent Antiviral Response Than Toll-Like Receptor 41 , 2003, The Journal of Immunology.

[120]  M. Smyth,et al.  Functional interactions between dendritic cells and NK cells during viral infection , 2003, Nature Immunology.

[121]  J. Shellito,et al.  Increased Host Resistance against Pneumocystis carinii Pneumonia in γδ T-Cell-Deficient Mice: Protective Role of Gamma Interferon and CD8+ T Cells , 2002, Infection and Immunity.

[122]  M. Zasloff Antimicrobial peptides of multicellular organisms , 2002, Nature.

[123]  T. Standiford,et al.  γδ-T Cells Are Critical for Survival and Early Proinflammatory Cytokine Gene Expression During Murine Klebsiella Pneumonia1 , 2000, The Journal of Immunology.

[124]  M. Lohmann‐Matthes,et al.  Local activation of nonspecific defense against a respiratory model infection by application of interferon-gamma: comparison between rat alveolar and interstitial lung macrophages. , 2000, American journal of respiratory cell and molecular biology.

[125]  R. Lehrer,et al.  Mouse neutrophils lack defensins , 1992, Infection and immunity.

[126]  R I Lehrer,et al.  Direct inactivation of viruses by human granulocyte defensins , 1986, Journal of virology.

[127]  Coral Fustero Torre,et al.  Bioengineering the Lung : Molecules , Materials , Matrix , Morphology , and Mechanics Lipoxin A 4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa , 2016 .

[128]  A. Karadağ,et al.  The evaluation of serum surfactant protein D (SP-D) levels as a biomarker of lung injury in tuberculosis and different lung diseases. , 2014, Clinical laboratory.

[129]  T. Mak,et al.  Infection Klebsiella Defense against Lipocalin 2 Is Required for Pulmonary Host , 2009 .

[130]  J. Wright Immunoregulatory functions of surfactant proteins , 2005, Nature Reviews Immunology.