1677Macrophage migration inhibitory factor (MIF) promotes clearance of pneumococcal colonization
نویسندگان
چکیده
Background. Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia (CAP). Methods. Since Streptococcus pneumoniae is the leading cause of CAP and nasal carriage a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. Results. MIF-deficient mice (Mif ) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared, to 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 monocyte chemotactic protein-1 (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 p38MAPK 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 antibody 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. Conclusion. 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. Disclosures. All authors: No reported disclosures.
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