Bacterial Adherence and Dwelling Probability: Two Drivers of Early Alveolar Infection by Streptococcus pneumoniae Identified in Multi-Level Mathematical Modeling

Pneumococcal infection is the most frequent cause of pneumonia, and one of the most prevalent diseases worldwide. The population groups at high risk of death from bacterial pneumonia are infants, elderly and immunosuppressed people. These groups are more vulnerable because they have immature or impaired immune systems, the efficacy of their response to vaccines is lower, and antibiotic treatment often does not take place until the inflammatory response triggered is already overwhelming. The immune response to bacterial lung infections involves dynamic interactions between several types of cells whose activation is driven by intracellular molecular networks. A feasible approach to the integration of knowledge and data linking tissue, cellular and intracellular events and the construction of hypotheses in this area is the use of mathematical modeling. For this paper, we used a multi-level computational model to analyse the role of cellular and molecular interactions during the first 10 h after alveolar invasion of Streptococcus pneumoniae bacteria. By “multi-level” we mean that we simulated the interplay between different temporal and spatial scales in a single computational model. In this instance, we included the intracellular scale of processes driving lung epithelial cell activation together with the scale of cell-to-cell interactions at the alveolar tissue. In our analysis, we combined systematic model simulations with logistic regression analysis and decision trees to find genotypic-phenotypic signatures that explain differences in bacteria strain infectivity. According to our simulations, pneumococci benefit from a high dwelling probability and a high proliferation rate during the first stages of infection. In addition to this, the model predicts that during the very early phases of infection the bacterial capsule could be an impediment to the establishment of the alveolar infection because it impairs bacterial colonization.

[1]  E. Tuomanen,et al.  The pneumococcus: epidemiology, microbiology, and pathogenesis. , 2013, Cold Spring Harbor perspectives in medicine.

[2]  G. Diamond,et al.  The innate immune response of the respiratory epithelium , 2000, Immunological reviews.

[3]  T. Martin,et al.  Innate immunity in the lungs. , 2005, Proceedings of the American Thoracic Society.

[4]  Eshel Ben-Jacob,et al.  The physics of bacterial decision making , 2014, Front. Cell. Infect. Microbiol..

[5]  A. Hakansson,et al.  Streptococcus pneumoniae biofilm formation and dispersion during colonization and disease , 2015, Front. Cell. Infect. Microbiol..

[6]  E. Pamer,et al.  Monocyte recruitment during infection and inflammation , 2011, Nature Reviews Immunology.

[7]  Xuedong Zhou,et al.  Nanotechnology strategies for antibacterial and remineralizing composites and adhesives to tackle dental caries. , 2015, Nanomedicine.

[8]  P. Jani,et al.  Inflammatory mechanisms in the lung , 2008, Journal of inflammation research.

[9]  A. Hoffmann,et al.  The I (cid:1) B –NF-(cid:1) B Signaling Module: Temporal Control and Selective Gene Activation , 2022 .

[10]  Aras Kadioglu,et al.  Capsule Type of Streptococcus pneumoniae Determines Growth Phenotype , 2012, PLoS pathogens.

[11]  Jeffrey N. Weiser,et al.  The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease , 2008, Nature Reviews Microbiology.

[12]  M. Foster,et al.  Scoping review to identify potential non-antimicrobial interventions to mitigate antimicrobial resistance in commensal enteric bacteria in North American cattle production systems , 2015, Epidemiology and Infection.

[13]  M. Sherman,et al.  Host defense in pulmonary alveoli. , 1992, Annual review of physiology.

[14]  P. Andrew,et al.  The innate immune response to pneumococcal lung infection: the untold story. , 2004, Trends in immunology.

[15]  T. Standiford,et al.  Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. , 1990, The Journal of clinical investigation.

[16]  G. Pozzi,et al.  Pneumococcal Surface Protein C Contributes to Sepsis Caused by Streptococcus pneumoniae in Mice , 2004, Infection and Immunity.

[17]  J. Larrick,et al.  Interleukin-7 and Immunosenescence , 2017, Journal of immunology research.

[18]  A. Hoffmann,et al.  Control of RelB during dendritic cell activation integrates canonical and non-canonical NF-κB pathways , 2012, Nature Immunology.

[19]  C. E. Perlman,et al.  Chloride-dependent secretion of alveolar wall liquid determined by optical-sectioning microscopy. , 2007, American journal of respiratory cell and molecular biology.

[20]  Martin Krzywinski,et al.  Points of Significance: Logistic regression , 2016, Nature Methods.

[21]  E. Tuomanen,et al.  Organ-specific models of Streptococcus pneumoniae Disease , 2003, Scandinavian journal of infectious diseases.

[22]  G. Ehrlich,et al.  Characterization, Distribution, and Expression of Novel Genes among Eight Clinical Isolates of Streptococcuspneumoniae , 2006, Infection and Immunity.

[23]  S. Sung,et al.  Significant Involvement of CCL2 (MCP‐1) in Inflammatory Disorders of the Lung , 2003, Microcirculation.

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

[25]  C. Orihuela,et al.  Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia , 2012, Experimental Gerontology.

[26]  Julio Vera,et al.  Third-Kind Encounters in Biomedicine: Immunology Meets Mathematics and Informatics to Become Quantitative and Predictive. , 2016, Methods in molecular biology.

[27]  T. Wizemann,et al.  Adherence of Streptococcus pneumoniae to Human Bronchial Epithelial Cells (BEAS-2B) , 1998, Infection and Immunity.

[28]  A. Sandgren,et al.  Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[29]  Christopher Lawrence,et al.  A computational model of invasive aspergillosis in the lung and the role of iron , 2016, BMC Systems Biology.

[30]  S. Evans,et al.  Bacterial Pneumonia in Patients with Cancer: Novel Risk Factors and Management. , 2017, Clinics in chest medicine.

[31]  V. Grantcharova,et al.  Therapeutically Targeting ErbB3: A Key Node in Ligand-Induced Activation of the ErbB Receptor–PI3K Axis , 2009, Science Signaling.

[32]  E. Goetzl,et al.  Unique determinants of alveolar macrophage spontaneous and chemokinetically stimulated migration. , 1978, Cellular immunology.

[33]  Denise E. Kirschner,et al.  Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-α and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection , 2013, PloS one.

[34]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[35]  Marc Thilo Figge,et al.  Agent-Based Model of Human Alveoli Predicts Chemotactic Signaling by Epithelial Cells during Early Aspergillus fumigatus Infection , 2014, PloS one.

[36]  M. Rehm,et al.  Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells , 2013, Cell Death and Differentiation.

[37]  A. Hocke,et al.  Illustration of Pneumococcal Polysaccharide Capsule during Adherence and Invasion of Epithelial Cells , 2005, Infection and Immunity.

[38]  F. Krombach,et al.  Cell size of alveolar macrophages: an interspecies comparison. , 1997, Environmental health perspectives.

[39]  M. Figge,et al.  Deciphering chemokine properties by a hybrid agent-based model of Aspergillus fumigatus infection in human alveoli , 2015, Front. Microbiol..

[40]  O. Wolkenhauer,et al.  Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures , 2017, Nature Communications.

[41]  M. Lipsitch,et al.  Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. J. Jedrzejas.  Pneumococcal Virulence Factors: Structure and Function , 2001, Microbiology and Molecular Biology Reviews.

[43]  J. Vera,et al.  Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection , 2017, Front. Physiol..

[44]  B. Pang,et al.  Residence of Streptococcus pneumoniae and Moraxella catarrhalis within polymicrobial biofilm promotes antibiotic resistance and bacterial persistence in vivo. , 2014, Pathogens and disease.

[45]  J. Verhoef,et al.  Streptococcus pneumoniae: virulence factors, pathogenesis, and vaccines , 1995, Microbiological reviews.

[46]  J. Gilsdorf,et al.  Community-acquired pneumonia in children. , 1987, Seminars in respiratory infections.

[47]  V. Vieland,et al.  Host-to-host variation of ecological interactions in polymicrobial infections , 2014, Physical biology.

[48]  A. El‐Solh,et al.  Etiology of severe pneumonia in the very elderly. , 2001, American journal of respiratory and critical care medicine.

[49]  Julio Vera,et al.  THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila – a systems biology study , 2017, Scientific Reports.

[50]  D. Lauffenburger,et al.  The effect of alveolar macrophage chemotaxis on bacterial clearance from the lung surface. , 1988, The American review of respiratory disease.

[51]  J. Galagan,et al.  Pneumococcal Capsular Polysaccharide Structure Predicts Serotype Prevalence , 2009, PLoS pathogens.

[52]  K. Honda,et al.  Inefficient phagosome maturation in infant macrophages. , 2008, Biochemical and biophysical research communications.

[53]  Olaf Wolkenhauer,et al.  A system biology approach to understand functional activity of cell communication systems. , 2008, Methods in cell biology.

[54]  H. Marriott,et al.  Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing , 2013, Clinical and experimental immunology.

[55]  D. Kuhns,et al.  Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections , 2003, The Journal of experimental medicine.

[56]  S B Charnick,et al.  Computer simulations of cell-target encounter including biased cell motion toward targets: single and multiple cell-target simulations in two dimensions. , 1991, Bulletin of mathematical biology.

[57]  Y. Oh,et al.  NF‐κB Activation Pathway is Essential for the Chemokine Expression in Intestinal Epithelial Cells Stimulated with Clostridium difficile Toxin A , 2006, Scandinavian journal of immunology.

[58]  R. Ramphal,et al.  Toll-like receptor 5 (TLR5), IL-1β secretion, and asparagine endopeptidase are critical factors for alveolar macrophage phagocytosis and bacterial killing , 2012, Proceedings of the National Academy of Sciences.

[59]  T. Mitchell,et al.  Pneumolysin Activates Macrophage Lysosomal Membrane Permeabilization and Executes Apoptosis by Distinct Mechanisms without Membrane Pore Formation , 2014, mBio.

[60]  J. Dauber,et al.  Chemotactic activity of guinea pig alveolar macrophages. , 1978, The American review of respiratory disease.

[61]  J. Hogg,et al.  Monocyte recruitment into the lungs in pneumococcal pneumonia. , 2004, American journal of respiratory cell and molecular biology.

[62]  Ph.D. Joseph Heitman M.D.,et al.  Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases , 2004, Mycopathologia.

[63]  J. Glass,et al.  Genome Sequence of Avery's Virulent Serotype 2 Strain D39 of Streptococcus pneumoniae and Comparison with That of Unencapsulated Laboratory Strain R6 , 2006, Journal of bacteriology.

[64]  S. Amini,et al.  Monocyte chemoattractant protein-1 (MCP-1): an overview. , 2009, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[65]  Matthias Ochs,et al.  The number of alveoli in the human lung. , 2004, American journal of respiratory and critical care medicine.

[66]  J. V. van Dijl,et al.  How Does Streptococcus pneumoniae Invade the Brain? , 2016, Trends in microbiology.

[67]  T. Cherian,et al.  Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates , 2009, The Lancet.

[68]  A. Athamna,et al.  Enzyme-linked immunosorbent assay for quantitation of attachment and ingestion stages of bacterial phagocytosis , 1988, Journal of clinical microbiology.

[69]  J. Mizgerd.  Molecular mechanisms of neutrophil recruitment elicited by bacteria in the lungs. , 2002, Seminars in immunology.

[70]  Sam P. Brown,et al.  Within-Host Competition Drives Selection for the Capsule Virulence Determinant of Streptococcus pneumoniae , 2010, Current Biology.

[71]  B. Spratt,et al.  Temporal and geographic stability of the serogroup-specific invasive disease potential of Streptococcus pneumoniae in children. , 2004, The Journal of infectious diseases.

[72]  Y. Shyy,et al.  Activation of MCP-1 gene expression is mediated through multiple signaling pathways. , 1993, Biochemical and biophysical research communications.

[73]  T. Welte,et al.  Important Role for CC Chemokine Ligand 2-Dependent Lung Mononuclear Phagocyte Recruitment to Inhibit Sepsis in Mice Infected with Streptococcus pneumoniae 1 , 2009, The Journal of Immunology.

[74]  W. L. Jorgensen,et al.  Macrophage Migration Inhibitory Factor Is Detrimental in Pneumococcal Pneumonia and a Target for Therapeutic Immunomodulation. , 2015, The Journal of infectious diseases.

[75]  E. Tuomanen.  Molecular and cellular biology of pneumococcal infection. , 1999, Current opinion in microbiology.

[76]  K. O'Brien,et al.  The fundamental link between pneumococcal carriage and disease , 2012, Expert review of vaccines.

[77]  A. Hoffmann,et al.  The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. , 2002, Science.

[78]  B. Levin,et al.  The ecology of nasal colonization of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus: the role of competition and interactions with host's immune response , 2010, BMC Microbiology.

[79]  E. Miyaji,et al.  Characterization of Protective Mucosal and Systemic Immune Responses Elicited by Pneumococcal Surface Protein PspA and PspC Nasal Vaccines against a Respiratory Pneumococcal Challenge in Mice , 2009, Clinical and Vaccine Immunology.

[80]  S. Harrison,et al.  Structure of an IκBα/NF-κB Complex , 1998, Cell.

[81]  B. Maycher,et al.  Radiological imaging in pneumonia: recent innovations , 2007, Current opinion in pulmonary medicine.

[82]  N. Suttorp,et al.  Streptococcus pneumoniae induced c-Jun-N-terminal kinase- and AP-1 -dependent IL-8 release by lung epithelial BEAS-2B cells , 2006, Respiratory research.

[83]  D. Lamb,et al.  Intra-alveolar macrophage numbers in current smokers and non-smokers: a morphometric study of tissue sections. , 1992, Thorax.

[84]  S. Schuster,et al.  Deciphering the Counterplay of Aspergillus fumigatus Infection and Host Inflammation by Evolutionary Games on Graphs , 2016, Scientific Reports.

[85]  O. Wolkenhauer,et al.  Kinetic modeling-based detection of genetic signatures that provide chemoresistance via the E2F1-p73/DNp73-miR-205 network. , 2013, Cancer research.

[86]  Y. Wang,et al.  Lipopolysaccharide-induced MCP-1 gene expression in rat tubular epithelial cells is nuclear factor-kappaB dependent. , 2000, Kidney international.

[87]  Tuomanen Ei,et al.  Molecular and cellular biology of pneumococcal infection. , 1997 .

[88]  M. Ramirez,et al.  Heterogeneity of pneumococcal phase variants in invasive human infections , 2006, BMC Microbiology.

[89]  D. S. Broomhead,et al.  Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription , 2009, Science.

[90]  S. Jeyaseelan,et al.  Neutrophil Recruitment to the Lungs during Bacterial Pneumonia , 2008, Infection and Immunity.

[91]  Sushmita Paul,et al.  Model-based genotype-phenotype mapping used to investigate gene signatures of immune sensitivity and resistance in melanoma micrometastasis , 2016, Scientific Reports.

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

[93]  S. Holgate,et al.  The airway epithelium: Structural and functional properties in health and disease , 2003, Respirology.

[94]  B. Foxman,et al.  Co-colonization by Streptococcus pneumoniae and Staphylococcus aureus in the throat during acute respiratory illnesses , 2016, Epidemiology and Infection.

[95]  H. Wagner,et al.  Toll-Like Receptor 2 Participates in Mediation of Immune Response in Experimental Pneumococcal Meningitis1 , 2003, The Journal of Immunology.

[96]  M. Hickey,et al.  Imaging inflammatory leukocyte recruitment in kidney, lung and liver—challenges to the multi‐step paradigm , 2013, Immunology and cell biology.