Abstract
Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection.
Highlights
The respiratory tract is a major portal of entry for airborne pathogens
These results are in line with an earlier study showing that increased numbers of dendritic cells (DCs) in the lungs of mice after treatment with FMS-like tyrosine kinase 3 ligand (Flt3L), which is a hemopoietic growth factor required for DC development in peripheral lymphoid tissue (Liu and Nussenzweig, 2010), significantly increased mortality and morbidity of mice challenged intranasally with pneumococci (Winter et al, 2007)
The improved control of S. pneumoniae infection after DC depletion observed in our study was neither mediated by an increased recruitment of cells involved in bacterial clearance at the site of infection nor by increased bactericidal capacity of neutrophils in the absence of DCs as recently reported in an experimental mouse model of Yersinia enterocolitica (Autenrieth et al, 2012)
Summary
The respiratory tract is a major portal of entry for airborne pathogens. The most common cause of respiratory tract infections worldwide is Streptococcus pneumoniae (van der Poll and Opal, 2009). Colonization of the human nasopharynx is the first step in the interaction between S. pneumoniae and the human host (Kadioglu and Andrew, 2004). From this location, the bacterium can spread to the lungs causing pneumonia, or further disseminate systemically causing invasive diseases. Mature DCs migrate via the afferent lymphatic vessels into the draining mediastinal lymph nodes, where they can activate antigen-specific T lymphocytes (Banchereau et al, 2000). Airway DCs undergo maturation and rapidly migrate to the T cell area of the draining mediastinal lymph nodes (Xia et al, 1995).
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