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 (CAP). 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. 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 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 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. 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.

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

“…The observation that MIF is a genetic marker of morbidity and mortality of pneumococcal meningitis is in line with the results obtained in animal models of sepsis and in clinical studies that have linked high levels of MIF with life-threatening bacterial infections (21,22,(46)(47)(48)(49). In a murine model of pneumococcal colonization, the clearance of pneumococci from the nasopharynx, a critical step in the pathogenesis of invasive pneumococcal diseases, was more rapid in wild-type mice than in MIF-deficient mice (45). This finding suggested that MIF might be a protective factor against pneumococcal diseases.…”

Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin

“…Colonization studies in mice have shown that the increased inflammation induced by its sole toxin, pneumolysin, accelerates the eventual clearance of the organism from its niche on the mucosal surface of the URT (Das et al, 2014; Matthias et al, 2008; van Rossum et al, 2005). This raises the question of why an organism dependent on a commensal lifestyle expresses a toxin that is both damaging to its obligate host and promotes its clearance (Weiser, 2010).…”

Mechanisms of Bacterial Colonization of the Respiratory Tract

“…Expression of MARCO (macrophage receptor with collagenous structure), though not directly responsible for pneumococcal uptake by upper respiratory tract macrophages, contributes to monocyte and macrophage recruitment, Ccl2 upregulation, and clearance of pneumococcal carriage (27). Macrophage migration inhibitory factor is also required during pneumococcal colonization to sustain the presence of macrophages, Ccl2 upregulation, and clearance (22). Expression of the microRNA miR-155 also contributes to Th17 induction and macrophage recruitment during pneumococcal carriage (117).…”

“…Paradoxically, macrophage recruitment, and eventual clearance, requires pneumococcal expression of its toxin, pneumolysin (22). It may seem counterintuitive for a colonizing organism to induce the specific host response that clears it, but it is possible that persistence in the respiratory tract is sacrificed at the expense of inducing a more robust inflammatory response, which could promote nutrient acquisition and transmission to a new host (129).…”