title: Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization.
abstract: Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and dasrit@mail.med.upenn.edu.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and.
authors.forename: Meredith I
authors.initials: MI
authors.lastname: LaRose
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Hergott
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, CT 06510.
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, CT 06510.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009305:Nasopharynx / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D010766:Phosphorylation / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D013301:Streptolysins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse