Allergic lung inflammation alters neither susceptibility to Streptococcus pneumoniae infection nor inducibility of innate resistance in mice

Abstract

Background: Protective host responses to respiratory pathogens are typically characterized by inflammation. However, lung inflammation is not always protective and it may even become deleterious to the host. We have recently reported substantial protection against Streptococcus pneumoniae (pneumococcal) pneumonia by induction of a robust inflammatory innate immune response to an inhaled bacterial lysate. Conversely, the allergic inflammation associated with asthma has been proposed to promote susceptibility to pneumococcal disease. This study sought to determine whether preexisting allergic lung inflammation influences the progression of pneumococcal pneumonia or reduces the inducibilty of protective innate immunity against bacteria.

Methods: To compare the effect of different inflammatory and secretory stimuli on defense against pneumonia, intraperitoneally ovalbumin-sensitized mice were challenged with inhaled pneumococci following exposure to various inhaled combinations of ovalbumin, ATP, and/or a bacterial lysate. Thus, allergic inflammation, mucin degranulation and/or stimulated innate resistance were induced prior to the infectious challenge. Pathogen killing was evaluated by assessing bacterial CFUs of lung homogenates immediately after infection, the inflammatory response to the different conditions was evaluated by measurement of cell counts of bronchoalveolar lavage fluid 18 hours after challenge, and mouse survival was assessed after seven days.

Results: We found no differences in survival of mice with and without allergic inflammation, nor did the induction of mucin degranulation alter survival. As we have found previously, mice treated with the bacterial lysate demonstrated substantially increased survival at seven days, and this was not altered by the presence of allergic inflammation or mucin degranulation. Allergic inflammation was associated with predominantly eosinophilic infiltration, whereas the lysate-induced response was primarily neutrophilic. The presence of allergic inflammation did not significantly alter the neutrophilic response to the lysate, and did not affect the induced bacterial killing within the lungs.

Conclusion: These results suggest that allergic airway inflammation neither promotes nor inhibits progression of pneumococcal lung infection in mice, nor does it influence the successful induction of stimulated innate resistance to bacteria.

Figure 1

Allergic lung inflammation neither promotes nor suppresses S. pneumoniae pneumonia-associated mortality. Survival of mice seven days after challenge with high or low dose S. pneumoniae in the presence or absence of allergic inflammation (6 mice/group).

Figure 2

Allergic inflammation and induced secretion affect neither survival nor pathogen burden in S. pneumoniae pneumonia. (A) Survival of ovalbumin-sensitized mice 7 days after challenge with intermediate dose (1.6 × 10¹⁰ CFU/ml) S. pneumoniae after induction of allergic inflammation by inhaled ovalbumin and/or secretion by inhaled ATP, as indicated (16 mice/group). There was no statistically significant difference in survival in any group compared to naive (OVA-, ATP-) mice. (B) Bacterial counts of lung homgenates immediately after pneumococcal challenge (1.6 × 10¹⁰ CFU/ml) of ovalbumin-sensitized mice, with or without induction of allergic inflammation and/or secretion (3 mice/group).

Figure 3

NTHi lysate protects against S. pneumoniae pneumonia in the presence of non-protective allergic inflammation. (A) Survival of ovalbumin-sensitized mice seven days after challenge with S. pneumoniae (6.8 × 10¹⁰ CFU/ml) following inhalation of ovalbumin and/or NTHi lysate prior to challenge (7 mice/group, *p = 0.01). (B) Survival of ovalbumin-sensitized mice seven days after challenge with S. pneumoniae (2.0 × 10¹⁰ CFU/ml) following inhalation of ovalbumin and/or NTHi lysate, with or without inhaled ATP exposure prior to challenge (6 mice/group, *p < 0.05). (C) Bacterial counts of lung homogenates immediately after pneumococcal challenge (1.2 × 10¹⁰ CFU/ml) of ovalbumin-sensitized mice, with or without induction of allergic inflammation and/or secretion and protective lysate exposure (3 mice/group, *p < 0.001 compared to mice not receiving NTHi treatment, mean ± SEM). OVA: inhaled ovalbumin 3 d prior to infection; ATP: inhaled ATP 5 min prior to infection; NTHi: inhaled NTHi lysate 1 d prior to infection. Figures shown are representative of at least three experiments.

Figure 4

Leukocyte infiltration following various inflammatory stimuli. Differential cell counts were performed on bronchoalveolar lavage fluid from mice following treatment with different combinations of inflammatory stimuli without (upper panel) or with (lower panel) infection with S. pneumoniae (3.2 × 10¹⁰ CFU/ml) 18 h earlier. The experiments were performed simultaneously with identical treatments, except for the infectious challenge. (3 mice/group, mean ± SEM).