Article

Neutrophil-toxin interactions promote antigen delivery and mucosal clearance of Streptococcus pneumoniae.

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 5.52). 06/2008; 180(9):6246-54.
Source: PubMed

ABSTRACT Delivery of Ag to inductive sites, such as nasal-associated lymphoid tissue (NALT) or GALT, is thought to promote mucosal immunity. Host and microbial factors that contribute to this process were investigated during model murine airway colonization by the pathogen Streptococcus pneumoniae. Colonization led to the deposition of released bacterial capsular Ag in the NALT in a manner consistent with trafficking through M cells. This Ag was derived from processing of bacteria in the lumen of the paranasal spaces rather than through invasion or sampling of intact bacteria. Neutrophils, which are recruited to the paranasal spaces where they associate with and may degrade bacteria, were required for efficient Ag delivery. Maximal Ag delivery to the NALT also required expression of the bacterial toxin pneumolysin. Pneumolysin and pneumolysin-expressing bacteria lysed neutrophils through pore formation in vitro. Accordingly, a pneumolysin-dependent loss of neutrophils, which correlated with the increased release of bacterial products, was observed in vivo. Thus, delivery of Ag to the NALT was enhanced by neutrophil-mediated generation of bacterial products together with bacterial-induced lysis of neutrophils. The impaired Ag delivery of pneumolysin-deficient bacteria was associated with diminished clearance from the mucosal surface. This study demonstrates how microbial-host interactions affect Ag delivery and the effectiveness of mucosal immunity.

0 Bookmarks
 · 
42 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Cellular and Infection Microbiology 01/2013; 3:21.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Polymicrobial interactions on mucosal surfaces can influence inflammation, immunity, and disease outcome. Here, we review how host responses to colonization in the upper respiratory tract with the bacterial pathogen Streptococcus pneumoniae can be altered by co-infection. Recent advances provide a mechanistic understanding of how mucosal immunity can be subverted at distinct immunological time-points during pneumococcal colonization by other pathogens such as Haemophilus influenzae, influenza type A and Staphylococcus aureus. These examples use animal models of co-infection to highlight how otherwise effective host responses can be rendered ineffective by co-infection, and vice versa. The complex microbial ecology of mucosal sites must be considered to fully understand how immune responses in a natural setting influence the outcome of host-pathogen interactions.
    Current opinion in immunology 06/2012; 24(4):417-23. · 10.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Streptococcus pneumoniae is a frequent asymptomatic colonizer of the nasopharyngeal niche, and only occasionally progresses towards infection. The burden of pneumococcal disease is particularly high in the elderly, and the mechanisms behind this increased susceptibility are poorly understood. Here we used a mouse model of pneumococcal carriage to study immunosenescence in the upper respiratory tract. Nasal associated lymphoid tissue (NALT) showed increased expression of Toll-like receptor 1, interleukin-1β, NLRp3 inflammasome, and CCL2 in naïve elderly compared to young animals. This suggests an increased pro-inflammatory expression profile in the NALT of aged mice at baseline. Simultaneously, we observed a more tolerogenic profile in respiratory epithelium of naïve elderly compared to young-adult mice with upregulation of the NF-κβ pathway inhibitor peroxisome proliferator-activated receptor-γ (PPARγ). After nasal instillation of pneumococci, pneumococcal colonization was prolonged in elderly mice compared to young-adults. Delay in clearance was associated with absent or delayed up-regulation of pro-inflammatory mediator(s) in the NALT, diminished influx of macrophages into the URT niche, absent down-regulation of PPARγ in respiratory epithelium, accompanied by diminished expression of cathelicidin (CRAMP) at the site of colonization. These findings suggest that unresponsiveness to pneumococcal challenge due to altered mucosal immune regulation is the key to increased susceptibility to disease in elderly.
    Infection and immunity 09/2013; · 4.21 Impact Factor

Full-text

View
0 Downloads
Available from