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: 4.92). 06/2008; 180(9):6246-54. DOI: 10.4049/jimmunol.180.9.6246
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "This phenomenon associated with DT treatment has been previously described by Tittel et al. (2012). As neutrophils are the most important innate immune cells for early defense against S. pneumoniae (Matthias et al., 2008; Standish and Weiser, 2009), it can be hypothesized that a higher amount of neutrophils present in the lungs of DT-treated mice previous to bacterial challenge can be responsible for the lower bacterial burdens observed in these animals at later time points. However, the fact that the amount of bacteria in the lungs at 24 h after intranasal challenge is comparable in PBS- and DT-treated mice gives clear indication that the greater amount of neutrophils in the lungs of the later mice is not responsible for the superior resistance of these animals. "
    [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 06/2013; 3:21. DOI:10.3389/fcimb.2013.00021 · 3.72 Impact Factor
  • Source
    • "Pneumococcal infections are controlled by host neutrophils, which kill this pathogen via opsonophagocytosis (OPH), a process that requires opsonization of bacteria by the complement system (Dalia et al., 2010; Lysenko et al., 2007; Matthias et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The complement system, which functions by lysing pathogens directly or by promoting their uptake by phagocytes, is critical for controlling many microbial infections. Here, we show that in Streptococcus pneumoniae, increasing bacterial chain length sensitizes this pathogen to complement deposition and subsequent uptake by human neutrophils. Consistent with this, we show that minimizing chain length provides wild-type bacteria with a competitive advantage in vivo in a model of systemic infection. Investigating how the host overcomes this virulence strategy, we find that antibody promotes complement-dependent opsonophagocytic killing of Streptococcus pneumoniae and lysis of Haemophilus influenzae independent of Fc-mediated effector functions. Consistent with the agglutinating effect of antibody, F(ab')(2) but not Fab could promote this effect. Therefore, increasing pathogen size, whether by natural changes in cellular morphology or via antibody-mediated agglutination, promotes complement-dependent killing. These observations have broad implications for how cell size and morphology can affect virulence among pathogenic microbes.
    Cell host & microbe 11/2011; 10(5):486-96. DOI:10.1016/j.chom.2011.09.009 · 12.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been proposed that the relative scarcity of Staphylococcus aureus and Streptococcus pneumoniae cocolonization in the nasopharynxes of humans can be attributed to hydrogen peroxide-mediated interference competition. Previously it has been shown in vitro that H(2)O(2) produced by S. pneumoniae is bactericidal to S. aureus. To ascertain whether H(2)O(2) has this inhibitory effect in the nasal passages of neonatal rats, colonization experiments were performed with S. aureus and S. pneumoniae. The results of these experiments with neonatal rats are inconsistent with the hypothesis that hydrogen peroxide-mediated killing of S. aureus by S. pneumoniae is responsible for the relative scarcity of cocolonization by these bacteria. In mixed-inoculum colonization experiments and experiments where S. aureus invaded the nasopharynxes of rats with established S. pneumoniae populations, the density of S. aureus did not differ whether the S. pneumoniae strain was H(2)O(2) secreting or non-H(2)O(2) secreting (SpxB). Moreover, the advantage of catalase production by S. aureus in competition with a non-catalase-producing strain (KatA) during nasal colonization was no greater in the presence of H(2)O(2)-producing S. pneumoniae than in the presence of non-H(2)O(2)-producing S. pneumoniae.
    Journal of bacteriology 12/2008; 191(2):571-5. DOI:10.1128/JB.00950-08 · 2.81 Impact Factor
Show more