Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

ABSTRACT Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae.

[1]  R. Wilson,et al.  Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses , 2014, Mucosal Immunology.

[2]  P. Thomas,et al.  Depletion of Alveolar Macrophages during Influenza Infection Facilitates Bacterial Superinfections , 2013, The Journal of Immunology.

[3]  W. Lim,et al.  Serotype prevalence in adults hospitalised with pneumococcal non-invasive community-acquired pneumonia , 2012, Thorax.

[4]  C. Orihuela,et al.  Changes in Capsular Serotype Alter the Surface Exposure of Pneumococcal Adhesins and Impact Virulence , 2011, PloS one.

[5]  Jeremy S. Brown,et al.  Protective Contributions against Invasive Streptococcus pneumoniae Pneumonia of Antibody and Th17-Cell Responses to Nasopharyngeal Colonisation , 2011, PloS one.

[6]  A. van Belkum,et al.  Infection with Conditionally Virulent Streptococcus pneumoniae Δpab Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains , 2011, Infection and Immunity.

[7]  J. McCullers,et al.  Mathematical model of a three-stage innate immune response to a pneumococcal lung infection. , 2011, Journal of theoretical biology.

[8]  J. Dorca,et al.  Serotypes and genotypes of Streptococcus pneumoniae causing pneumonia and acute exacerbations in patients with chronic obstructive pulmonary disease. , 2011, The Journal of antimicrobial chemotherapy.

[9]  D. Metzger,et al.  Analysis of Murine Genetic Predisposition to Pneumococcal Infection Reveals a Critical Role of Alveolar Macrophages in Maintaining the Sterility of the Lower Respiratory Tract , 2011, Infection and Immunity.

[10]  J. Curtis,et al.  Cigarette Smoke Exposure Impairs Pulmonary Bacterial Clearance and Alveolar Macrophage Complement-Mediated Phagocytosis of Streptococcus pneumoniae , 2009, Infection and Immunity.

[11]  Jeremy S. Brown,et al.  The Streptococcuspneumoniae Capsule Inhibits Complement Activity and Neutrophil Phagocytosis by Multiple Mechanisms , 2009, Infection and Immunity.

[12]  J. Weiser,et al.  Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype , 2009, Infection and Immunity.

[13]  J. Tomás,et al.  Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. , 2008, Microbiology.

[14]  Brenton L. Scott,et al.  Stimulation of lung innate immunity protects against lethal pneumococcal pneumonia in mice. , 2008, American journal of respiratory and critical care medicine.

[15]  G. Jönsson,et al.  Impaired Opsonization with C3b and Phagocytosis of Streptococcus pneumoniae in Sera from Subjects with Defects in the Classical Complement Pathway , 2008, Infection and Immunity.

[16]  D. Metzger,et al.  Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection , 2008, Nature Medicine.

[17]  H. Marriott,et al.  THE ROLE OF THE MACROPHAGE IN LUNG DISEASE MEDIATED BY BACTERIA , 2007, Experimental lung research.

[18]  A. Nelson,et al.  Capsule Enhances Pneumococcal Colonization by Limiting Mucus-Mediated Clearance , 2006, Infection and Immunity.

[19]  Lester Kobzik,et al.  The macrophage scavenger receptor SR-AI/II and lung defense against pneumococci and particles. , 2006, American journal of respiratory cell and molecular biology.

[20]  W. Timens,et al.  Antimicrobial proteins and polypeptides in pulmonary innate defence , 2006, Respiratory research.

[21]  Jeremy S. Brown,et al.  Additive Inhibition of Complement Deposition by Pneumolysin and PspA Facilitates Streptococcus pneumoniae Septicemia 1 , 2005, The Journal of Immunology.

[22]  T. Mitchell,et al.  Innate Immune Defense against Pneumococcal Pneumonia Requires Pulmonary Complement Component C3 , 2005, Infection and Immunity.

[23]  K. Tryggvason,et al.  The Scavenger Receptor MARCO Is Required for Lung Defense against Pneumococcal Pneumonia and Inhaled Particles , 2004, The Journal of experimental medicine.

[24]  T. Ganz,et al.  Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae , 2004, BMC infectious diseases.

[25]  P. Ince,et al.  Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection 1 , 2003, The Journal of Immunology.

[26]  T. van der Poll,et al.  Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. , 2003, American journal of respiratory and critical care medicine.

[27]  W. Seeger,et al.  Role of resident alveolar macrophages in leukocyte traffic into the alveolar air space of intact mice. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[28]  R C Read,et al.  Macrophage defences against respiratory tract infections. , 2002, British medical bulletin.

[29]  T. van der Poll,et al.  Depletion of Alveolar Macrophages Exerts Protective Effects in Pulmonary Tuberculosis in Mice1 , 2001, The Journal of Immunology.

[30]  R. Read,et al.  Intracellular Trafficking and Killing ofStreptococcus pneumoniae by Human Alveolar Macrophages Are Influenced by Opsonins , 2000, Infection and Immunity.

[31]  E. Pesanti,et al.  Nonphagocytic clearance of Staphylococcus aureus from murine lungs , 1982, Infection and immunity.

[32]  E. Goldstein,et al.  Murine pulmonary alveolar macrophages: rates of bacterial ingestion, inactivation, and destruction. , 1976, The Journal of infectious diseases.

[33]  E. Kass,et al.  THE ROLE OF THE ALVEOLAR MACROPHAGE IN THE CLEARANCE OF BACTERIA FROM THE LUNG , 1964, The Journal of experimental medicine.

[34]  W. Wood,et al.  THE INHIBITION OF SURFACE PHAGOCYTOSIS BY THE CAPSULAR "SLIME LAYER" OF PNEUMOCOCCUS TYPE III , 1949, The Journal of experimental medicine.

[35]  H. Marriott,et al.  Streptococcus pneumoniae: the role of apoptosis in host defense and pathogenesis. , 2006, The international journal of biochemistry & cell biology.