Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae

<p>Abstract</p> <p>Background</p> <p>The risk of mortality from pneumonia caused by <it>Streptococcus pneumoniae </it>is increased in patients with cirrhosis. However, the specific pneumococcal virulence factors and host immune defects responsible for this finding have not been clearly established. This study used a cirrhotic rat model of pneumococcal pneumonia to identify defect(s) in innate pulmonary defenses in the cirrhotic host and to determine the impact of the pneumococcal toxin pneumolysin on these defenses in the setting of severe cirrhosis.</p> <p>Results</p> <p>No cirrhosis-associated defects in mucociliary clearance of pneumococci were found in these studies, but early intrapulmonary killing of the organisms before the arrival of neutrophils was significantly impaired. This defect was exacerbated by pneumolysin production in cirrhotic but not in control rats. Neutrophil-mediated killing of a particularly virulent type 3 pneumococcal strain also was significantly diminished within the lungs of cirrhotic rats with ascites. Levels of lysozyme and complement component C3 were both significantly reduced in bronchoalveolar lavage fluid from cirrhotic rats. Finally, complement deposition was reduced on the surface of pneumococci recovered from the lungs of cirrhotic rats in comparison to organisms recovered from the lungs of control animals.</p> <p>Conclusion</p> <p>Increased mortality from pneumococcal pneumonia in this cirrhotic host is related to defects in both early pre-neutrophil- and later neutrophil-mediated pulmonary killing of the organisms. The fact that pneumolysin production impaired pre-neutrophil-mediated pneumococcal killing in cirrhotic but not control rats suggests that pneumolysin may be particularly detrimental to this defense mechanism in the severely cirrhotic host. The decrease in neutrophil-mediated killing of pneumococci within the lungs of the cirrhotic host is related to insufficient deposition of host proteins such as complement C3 on their surfaces. Pneumolysin likely plays a role in complement consumption within the lungs. Our studies, however, were unable to determine whether pneumolysin more negatively impacted this defense mechanism in cirrhotic than in control rats. These findings contribute to our understanding of the defects in innate pulmonary defenses that lead to increased mortality from pneumococcal pneumonia in the severely cirrhotic host. They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis.</p

Total number of pneumococci recovered from individual rats' lungs five hours after an intranasal challenge with 1 × 10cfu of pneumolysin sufficient (Ply+) or pneumolysin deficient (Ply-)

<p><b>Copyright information:</b></p><p>Taken from "Cirrhosis-induced defects in innate pulmonary defenses against "</p><p>http://www.biomedcentral.com/1471-2180/7/94</p><p>BMC Microbiology 2007;7():94-94.</p><p>Published online 23 Oct 2007</p><p>PMCID:PMC2140065.</p><p></p> Horizontal bars represent the mean values for each group

Quantification of complement deposition on pneumococci recovered from the lungs of cirrhotic and control rats 15 min after infection with 1 × 10cfu of ATCC 6303

<p><b>Copyright information:</b></p><p>Taken from "Cirrhosis-induced defects in innate pulmonary defenses against "</p><p>http://www.biomedcentral.com/1471-2180/7/94</p><p>BMC Microbiology 2007;7():94-94.</p><p>Published online 23 Oct 2007</p><p>PMCID:PMC2140065.</p><p></p> Flow cytometry was used to determine: (A) – percentage of pneumococci positive for bound C3; (B) – mean fluorescent intensity of pneumococci with bound C3; and (C) – deposition index calculated by multiplying the percentage of pneumococci positive for C3 by their fluorescent intensity. Both the mean fluorescent intensity (*: = 0.04) and deposition index (**: = 0.01) were significantly lower for organisms recovered from the lungs of cirrhotic vs. control rats