title: Analysis of murine genetic predisposition to pneumococcal infection reveals a critical role of alveolar macrophages in maintaining the sterility of the lower respiratory tract.
abstract: The study of pathogenic mechanisms of disease can be greatly facilitated by studying genetic differences in susceptibility to infection. In the present study, we compared the severity of pneumococcal infection in C57BL/6 (B6) and 129Sv mice. The results showed that 129Sv mice were remarkably more susceptible to pneumococcal infection than B6 mice. Bacterial clearance, proinflammatory mediators, leukocyte recruitment, and phagocyte activities were measured to examine potential immune factors associated with differences in susceptibility to pneumococcal infection. The greater susceptibility of 129Sv mice was associated only with inadequate alveolar macrophage bacterial killing, as indicated by significantly decreased initial bacterial clearance from the respiratory tract. Effective pneumococcal clearance was not dependent upon Toll-like receptor 2 (TLR2) expression, oxidative stress, or matrix metallopeptidase 12 (MMP-12) expression. Furthermore, phagocytosis analysis suggested that the deficiency found in 129Sv alveolar macrophages was not due to a lack of bacterial recognition but, rather, to reduced bacterial uptake. In conclusion, our findings indicate a crucial role of alveolar macrophage phagocytosis during innate defense against pneumococcal infection, which may explain the association of host genetic risk factors with predisposition to pneumococcal infection.
authors.affiliation: Center for Immunology and Microbial Disease, MC-151, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. Sunk@mail.amc.edu
authors.forename: Keer
authors.initials: K
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Gan
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000818:Animals; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011018:Pneumonia, Pneumococcal / Q000235:genetics* / Q000276:immunology / Q000382:microbiology