{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:41:45Z","timestamp":1790188905601,"version":"4.1.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2212\/\u2212) 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\u2212\/\u2212 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\u2013derived 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\u2212\/\u2212 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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1400133","type":"journal-article","created":{"date-parts":[[2014,6,16]],"date-time":"2014-06-16T14:19:10Z","timestamp":1402928350000},"page":"764-772","source":"Crossref","is-referenced-by-count":35,"title":["Macrophage Migration Inhibitory Factor Promotes Clearance of Pneumococcal Colonization"],"prefix":"10.1093","volume":"193","author":[{"given":"Rituparna","family":"Das","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith I","family":"LaRose","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B","family":"Hergott","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yale School of Medicine , New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Bucala","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yale School of Medicine , New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N","family":"Weiser","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,7,15]]},"reference":[{"key":"2025030707214762500_r1","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/S0140-6736(09)61204-6","article-title":"Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates","volume":"374","author":"O\u2019Brien","year":"2009","journal-title":"Lancet"},{"key":"2025030707214762500_r2","volume-title":"Active Bacterial Core Surveillance (ABCs) Report\u2014Emerging Infections Program Network: Streptococcus pneumoniae.","author":"Centers for Disease Control and Prevention","year":"2010"},{"key":"2025030707214762500_r3","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1056\/NEJMoa022678","article-title":"Effectiveness of pneumococcal polysaccharide vaccine in older adults","volume":"348","author":"Jackson","year":"2003","journal-title":"N. 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