Allergic Lung Inflammation Reduces Tissue Invasion and Enhances Survival from Pulmonary Pneumococcal Infection in Mice, Which Correlates with Increased Expression of Transforming Growth Factor β1 and SiglecF ^low Alveolar Macrophages

Abstract

Asthma is generally thought to confer an increased risk for invasive pneumococcal disease (IPD) in humans. However, recent reports suggest that mortality rates from IPD are unaffected in patients with asthma and that chronic obstructive pulmonary disease (COPD), a condition similar to asthma, protects against the development of complicated pneumonia. To clarify the effects of asthma on the subsequent susceptibility to pneumococcal infection, ovalbumin (OVA)-induced allergic lung inflammation (ALI) was induced in mice followed by intranasal infection with A66.1 serotype 3 Streptococcus pneumoniae. Surprisingly, mice with ALI were significantly more resistant to lethal infection than non-ALI mice. The heightened resistance observed following ALI correlated with enhanced early clearance of pneumococci from the lung, decreased bacterial invasion from the airway into the lung tissue, a blunted inflammatory cytokine and neutrophil response to infection, and enhanced expression of transforming growth factor ␤1 (TGF-␤1). Neutrophil depletion prior to infection had no effect on enhanced early bacterial clearance or resistance to IPD in mice with ALI. Although eosinophils recruited into the lung during ALI appeared to be capable of phagocytizing bacteria, neutralization of interleukin-5 (IL-5) to inhibit eosinophil recruitment likewise had no effect on early clearance or survival following infection. However, enhanced resistance was associated with an increase in levels of clodronatesensitive, phagocytic SiglecF low alveolar macrophages within the airways following ALI. These findings suggest that, while the risk of developing IPD may actually be decreased in patients with acute asthma, additional clinical data are needed to better understand the risk of IPD in patients with different asthma phenotypes. Streptococcus pneumoniae is a Gram-positive, extracellular bacterium commonly found in the upper respiratory tract and is recognized as the leading cause of community-acquired pneumonia worldwide (1). S. pneumoniae infections can range from asymptomatic carriage to more-severe outcomes such as otitis media, pneumonia, and pneumococcal meningitis. The capacity for invasion from a carrier state is directly related to the capsule polysaccharide serotype. Over 90 serotypes are known to exist (2), which complicates the clinical effectiveness of vaccination and emphasizes the importance of developing a better understanding of the immunological response to acute pneumococcal infections in the lung.Mortality following invasive pneumococcal infections is significantly higher among at-risk populations, such as the elderly or individuals with underlying medical conditions (3). Asthma has recently been identified as a significant risk factor for invasive pneumococcal disease (4-6). This increased risk has also been extended to other atopic conditions such as allergic rhinitis and hay fever (7), and the Advisory Committee on Immunization Practices has included individuals with asthma among those indicated for pneumococcal polysaccharid...

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection

“…We have previously reported that alveolar macrophages play an important role in early bacterial clearance (4, 28, 29). Indeed, depletion of alveolar macrophages during coinfection of AAD mice significantly reduced survival (Fig.…”

GM-CSF treatment prevents respiratory syncytial virus–induced pulmonary exacerbation responses in postallergic mice by stimulating alveolar macrophage maturation

“…TGF-b is abundantly produced during AAI and is dominantly present in post-AAI lungs. 35 TGF-b could suppress GM-CSF secretion by lung cells and hence inhibit post-AAI rAM maturation. Furthermore, a study by Sawada et al 36 reported the inhibitory effect of IL-4 on GM-CSF production.…”

Allergic Asthma Favors Brucella Growth in the Lungs of Infected Mice

“…Wildly conflicting results have been published on the impact of asthma on S. pneumoniae infection in mice. Intraperitoneally, OVA-sensitized mice have been reported to display reduced ( 74 ), similar ( 75 ), or enhanced ( 76 , 77 ) susceptibility to infection. The discrepancies between these results may be connected with the serotype of S. pneumoniae used, the sanitary level of the mice, or a delay between infection and asthma challenge.…”