Differential activation of the immune system by virulentStreptococcus pneumoniaestrains determines recovery or death of the host

Abstract

SUMMARYStreptococcus pneumoniae infection may result in asymptomatic carriage, mucosal or invasive disease. We hypothesize that self-limiting or fatal disease outcome follows infection with S. pneumoniae differential activation of the host immune response. BALB/c and C57BL/6 mice were inoculated intranasally with S. pneumoniae serotype 3 strain WU2 and serotype 14 strain DW14 and mortality, bacterial load, pathological changes in the lungs and cytokines mRNA levels in the spleen were analysed. No differences between the C57BL/6 and the BALB/c inbred mice were observed except for the severity of their lung pathology and IL-4 expression. Infection of the two mouse strains with S. pneumoniae WU2 resulted in sepsis and death that occurred within 4 days post-inoculation. This death was preceded, in both mouse strains, in an increase over time of the lung bacterial load and bacteraemia. The lung pathology was characterized by diffuse pneumonia with marked congestion of the lungs. Analysis of mRNA expression of cytokines in the spleen revealed no alterations in tumour necrosis factor (TNF)-α , transforming growth factor (TGF)-β , interleukin (IL)-12 and interferon (IFN)-γ and induction of IL-10 and IL-4. The two strains of mice survived infection with S. pneumoniae DW14. This was accompanied by a reduction over time of lung bacterial load and bacteraemia. The lung pathology was characterized by focal lymphocyte infiltration and preserved architecture of the organ. Analysis of mRNA expression of cytokines in the spleen revealed a significant decrease in the levels of TNF-α , TGF-β , IL-12 and IFN-γ mRNA expression, which usually precedes cytokine protein expression. Interestingly, a significant increase in the levels of IL-4 mRNA expression was found in BALB/c mice only. This study suggests that differential activation or evasion of cytokine expression by S. pneumoniae virulent strains determines disease outcome regardless of the host's immunogenetic background.

Analysis of Murine Genetic Predisposition to Pneumococcal Infection Reveals a Critical Role of Alveolar Macrophages in Maintaining the Sterility of the Lower Respiratory Tract

“…However, alveolar macrophages from B6 mice have increased phagocytic activity and oxidative burst compared with those from BALB/mice (22). These observations might explain the high level of resistance to pneumococcal infection of B6 and BALB/c mice (12,20). BALB/c mice actually have increased resistance to lethal pneumococcal infection compared to that of B6 mice due to their improved neutrophil activity (9).…”

“…Furthermore, phagocytosis analysis suggested that the deficiency found in 129Sv alveolar macrophages was not due to a lack of bacterial recognition but, rather, to reduced bacterial uptake. In conclusion, our findings indicate a crucial role of alveolar macrophage phagocytosis during innate defense against pneumococcal infection, which may explain the association of host genetic risk factors with predisposition to pneumococcal infection.There are over 90 Streptococcus pneumoniae serotypes, based on their capsular polysaccharide, and different serotypes vary in the ability to cause disease on the basis of the virulent factors expressed (19,20). On the other hand, host genetic components are also involved in the outcome of pneumococcal infection (2, 4, 22), and host immune status associated with age, respiratory viral infection, chronic diseases, and immunosuppression are all significant risk factors for the development of severe pneumococcal infection (13,16).…”

“…There are over 90 Streptococcus pneumoniae serotypes, based on their capsular polysaccharide, and different serotypes vary in the ability to cause disease on the basis of the virulent factors expressed (19,20). On the other hand, host genetic components are also involved in the outcome of pneumococcal infection (2, 4, 22), and host immune status associated with age, respiratory viral infection, chronic diseases, and immunosuppression are all significant risk factors for the development of severe pneumococcal infection (13,16).…”

Pneumococcal Interactions with Epithelial Cells Are Crucial for Optimal Biofilm Formation and Colonization In Vitro and In Vivo

“…Furthermore, our results demonstrate that the development of biofilm-specific properties, including antibiotic resistance, during biofilm formation on epithelial cells correlates directly with the ability of both clinical strains and isogenic mutants lacking factors involved in colonization to colonize the murine nasopharynx. In support of this, we showed that clinical isolates from children (EF3030 and BG8826), which effectively colonize the murine nasopharynx (13,42), formed biofilms of higher biomass and more developed architecture, with increased biofilm-specific antibacterial resistance on epithelial cells, than strains that colonize less effectively (D39, WU2, and SP670) and are more prone to disseminate to the bloodstream and cause septic in- fection (7,32,44,48,54). This difference in biofilm formation was not observed using abiotic surfaces.…”

Optimized Immune Response Elicited by a DNA Vaccine Expressing Pneumococcal Surface Protein A Is Characterized by a Balanced Immunoglobulin G1 (IgG1)/IgG2a Ratio and Proinflammatory Cytokine Production

“…Interleukin-12 (IL-12) deficiency has also been correlated with increased susceptibility to pneumococcal infections, presumably due to a deficient T-cell response (10). In mice, the development of disease and the host response to the pneumococcal challenge have been studied with different strains of wild-type (WT) and knockout (KO) animals (13,14,18,25,27), but all of these studies were performed with nonimmunized mice only and reported that resolution of infection in the naïve host is mediated primarily through phagocytosis and intracellular killing by neutrophils and macrophages, which are recruited to the site of infection in response to proinflammatory cytokine and interleukin release by T lymphocytes. In accordance with this, it has been suggested that gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) produced by NK and T cells have a crucial involvement not only in the natural host defense but also in acquired resistance against S. pneumoniae (12,24).…”