Enhanced vulnerability for Streptococcus pneumoniae sepsis during asplenia is determined by the bacterial capsule
Introduction
Individuals with asplenia are known to be at risk for post-splenectomy sepsis (PSS), which carries a high mortality of 50–70% (Cullingford et al., 1991, Hosea et al., 1981, Styrt, 1990, Altamura et al., 2001). Encapsulated bacteria are thought to be the responsible pathogens for PSS, since Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis account for more than half of septic episodes (Holdsworth et al. 1991). Although other microorganisms are considered to carry some risk as well (Lynch and Kapila, 1996, Styrt, 1990), all preventive strategies traditionally have focused on encapsulated pathogens (Mourtzoukou et al. 2008).
The importance of the spleen in host defense against encapsulated bacteria has been invigorated by several experimental models. The first in a series of animal studies was published in 1919, wherein rats proved to be more susceptible to bacterial infection after splenectomy than after orchidectomy (Morris and Bullock 1919). Subsequently, animal studies have focused on S. pneumoniae, using different routes of administration and different serotypes, all confirming the capacity of this bacterium to cause severe infection after removal of the spleen (Coil et al., 1978, Kuranaga et al., 2006, Loggie et al., 1985, Offenbartl et al., 1984, Shih-Ching et al., 2004). The mechanism of increased susceptibility to infection is thought to be related to the splenic efficient innate and adaptive immunological surveillance of the circulation (Cesta, 2006, Mebius and Kraal, 2005). Its specific role in the removal of encapsulated bacteria is related to marginal zone macrophages, which are able to detect and capture encapsulated bacteria (Koppel et al. 2005) and marginal zone B cells, which respond to capsule polysaccharide antigens by differentiating into IgM-producing memory B cells or antigen presenting cells.
Although the literature collectively describes an established role of encapsulated bacteria in severe infection after splenectomy, to the best of our knowledge the contribution of the bacterial capsule herein has never been studied directly. We sought to dissect the relative contribution of the pneumococcal capsule versus other virulence factors of the pneumococcus (not residing in the capsule) in the diminished resistance of asplenic mice by comparing the host response of splenectomized and sham-operated mice after pulmonary or systemic infection with wild-type (WT) or isogenic mutant S. pneumoniae lacking the polysaccharide capsule. We demonstrate for the first time that it is indeed the capsule of S. pneumoniae that is responsible for enhanced susceptibility to infection after splenectomy.
Section snippets
Animals
In all experiments, male, age matched, specific pathogen-free C57BL/6 mice (Charles River, Maastricht, Netherlands) were used. All experiments were approved by the Animal Care and Use Committee of the University of Amsterdam (Amsterdam, Netherlands).
Bacteria
S. pneumoniae strains used in this study were WT isolates D39 (serotype 2) and TIGR4 (serotype 4) and their isogenic capsule locus (cps) deletion mutants D39Δcps and TIGR4Δcps, which were constructed as described previously (Cron et al. 2009).
Splenectomy
Mice
Splenectomy results in an enhanced mortality after induction of pneumonia with D39 but not with D39Δcps
First we investigated the impact of splenectomy on the outcome of pneumonia with WT (serotype-2-encapsulated) D39. For this we infected mice intranasally with D39 at a dose known to be nonlethal to normal WT mice (4 × 105 CFU) (Dessing et al. 2008) two weeks after splenectomy (Splx-mice) or sham surgery (Sham-mice), and followed them for 48 h (Table 1A). As expected, all Sham-mice survived. In sharp contrast, 6 of 7 Splx-mice died within the 48-h observation period (P < 0.01 versus sham). Intranasal
Discussion
Asplenia renders the host at increased risk for pneumococcal pneumonia and sepsis with fatal outcome (Altamura et al., 2001, Cullingford et al., 1991, Hosea et al., 1981, Styrt, 1990). The bacterial capsule is considered an important virulence factor of S. pneumoniae in general and especially in asplenic patients. The pneumococcus expresses multiple virulence factors that are unrelated to the capsule (reviewed in Kadioglu et al. 2008). In the present study we addressed the question whether
Conclusion
Splenectomy results in a strongly increased susceptibility to severe infections caused by S. pneumoniae. We here demonstrate that pneumococcal strains that are lacking the capsule but still express other important virulence factors are rapidly cleared even in the absence of the spleen. As such, our data provide solid evidence that indeed the capsule has a prominent role in the enhanced vulnerability to pneumococcal disease in patients after splenectomy or with functional asplenia.
Acknowledgements
We thank Marieke ten Brink and Joost Daalhuisen for technical assistance during the animal experiments and Christa van der Gaast for technical assistance with the construction of mutants.
References (32)
- et al.
Overwhelming postsplenectomy infection
Infect. Dis. Clin. North Am.
(1996) - et al.
Splenectomy differentially influences immune responses in various tissue compartments of the body
Cytokine
(2004) - et al.
Pathogenesis, treatment, and prevention of pneumococcal pneumonia
Lancet
(2009) - et al.
Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance
Immunopharmacol. Immunotoxicol.
(2001) - et al.
Pneumococcal conjugate vaccines overcome splenic dependency of antibody response to pneumococcal polysaccharides
Infect. Immun.
(2001) - et al.
The role of the spleen in experimental pneumococcal bacteremia
J. Clin. Invest.
(1981) Normal structure, function, and histology of the spleen
Toxicol. Pathol.
(2006)- et al.
Increased susceptibility of splenectomized mice to infection after exposure to an aerosolized suspension of type III Streptococcus pneumoniae
Infect. Immun.
(1978) - et al.
Surface-associated lipoprotein PpmA of Streptococcus pneumoniae is involved in colonization in a strain-specific manner
Microbiology
(2009) - et al.
Severe late postsplenectomy infection
Br. J. Surg.
(1991)
Toll-like receptor 2 contributes to antibacterial defence against pneumolysin-deficient pneumococci
Cell. Microbiol.
CD14 facilitates invasive respiratory tract infection by Streptococcus pneumoniae
Am. J. Respir. Crit. Care Med.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances pulmonary defenses against pneumococcal infections after splenectomy
J. Trauma
Augmentation of alveolar macrophage phagocytic activity by granulocyte colony stimulating factor and interleukin-1: influence of splenectomy
J. Trauma
Postsplenectomy sepsis and its mortality rate: actual versus perceived risks
Br. J. Surg.
Opsonic requirements for intravascular clearance after splenectomy
N. Engl. J. Med.
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