No abstract

Streptococcus pneumoniae is a common cause of pneumonia and infective exacerbations of chronic lung disease, yet there are few data on how adaptive immunity can specifically prevent S. pneumoniae lung infection. We have used a murine model of nasopharyngeal colonization by the serotype 19F S. pneumoniae strain EF3030 followed by lung infection to investigate whether colonization protects against subsequent lung infection and the mechanisms involved. EF3030 colonization induced systemic and local immunoglobulin G against a limited number of S. pneumoniae protein antigens rather than capsular polysaccharide. During lung infection, previously colonized mice had increased early cytokine responses and neutrophil recruitment and reduced bacterial colony-forming units in the lungs and bronchoalveolar lavage fluid compared with control mice. Colonization-induced protection was lost when experiments were repeated in B-cell- or neutrophil-deficient mice. Furthermore, the improved interleukin (IL)-17 response to infection in previously colonized mice was abolished by depletion of CD4+ cells, and prior colonization did not protect against lung infection in mice depleted of CD4+ cells or IL17. Together these data show that naturally acquired protective immunity to S. pneumoniae lung infection requires both humoral and cell-mediated immune responses, providing a template for the design of improved vaccines that can specifically prevent pneumonia or acute bronchitis.

No abstract

Mesenchymal stromal cells (MSCs) are inherently tumor-homing and can be isolated, expanded and transduced, making them viable candidates for cell therapy. This tumor-tropism has been used to deliver anti-cancer therapies to various tumor models. In this study we sought to discover which molecules are the key effectors of human MSC tumor homing in vitro and using an in vivo murine model. Here we discover for the first time that Macrophage Migration Inhibitory Factor (MIF) is the key director of MSC migration and infiltration towards tumor cells. We have shown this major role for MIF using in vitro migration and invasion assays, in presence of different receptor inhibitors and achieving a drastic decrease in both processes using MIF inhibitor. Additionally, we demonstrate physical interaction between MIF and three receptors: CXCR2, CXCR4 and CD74. CXCR4 is the dominant receptor used by MIF in the homing tumor context, although some signaling is observed through CXCR2. We demonstrate downstream activation of the MAPK pathway necessary for tumor homing. Importantly we show that knock down of either CXCR4 or MIF abrogates MSC homing to tumors in an in vivo pulmonary metastasis model, confirming the in vitro 2D and 3D assays. This improved understanding of MSC tumor tropism will further enable development of novel cellular therapies for cancers.