Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung

Habibzay, Maryam; Saldana, JI; Goulding, John; Lloyd, Clare M.; Hussell, Tracy

doi:10.1038/mi.2012.28

Cited by 60 publications

(48 citation statements)

References 49 publications

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“…Thus, additional studies are under way to determine whether BAFF/APRIL and TLR signaling pathways are defective in asthmatic mice. An impairment in TLR responses in asthmatic mice that leads to defective bacterial clearance has been recently reported (52). It is therefore plausible that a similar TLR signaling impairment exists in our asthma/influenza model and is responsible for diminished mucosal antibody responses.…”

Section: Discussionmentioning

confidence: 84%

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Furuya

Roberts

Hurteau

et al. 2014

J Virol

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Asthma was the most common comorbidity observed among patients hospitalized with influenza A virus during the 2009 pandemic. However, little remains known about how the asthmatic phenotype influences protective immune responses against respiratory viral pathogens. Using the ovalbumin-induced allergic lung inflammation model, we found that asthmatic mice, unlike nonasthmatic mice, were highly susceptible to secondary heterologous virus challenge. While primary virus infection generated protective memory immune responses against homologous secondary virus challenge in both asthmatic and nonasthmatic mice, full protection against heterologous A/California/04/2009 (CA04) viral infection was observed only in nonasthmatic mice. Significant reductions in CA04-specific IgA, IgG, and IgM levels and in CA04-neutralizing activity of bronchoalveolar lavage fluid (BALF) was observed following secondary CA04 challenge of PR8-immunized asthmatic mice. Furthermore, transfer of immune BALF obtained from nonasthmatic, but not asthmatic, donors following secondary viral infection generated protection against CA04 in naive recipients. Nonspecific B-cell activation by CpG inoculation restored protection in PR8-immunized, CA04-challenged asthmatic mice. These results demonstrate a causal link between defective mucosal antibody responses and the heightened susceptibility of asthmatic mice to influenza infection and provide a mechanistic explanation for the observation that asthma was a major risk factor during the 2009 influenza pandemic. IMPORTANCEThe prevalence of asthma worldwide is increasing each year. Unfortunately, there is no cure for asthma. Asthmatic individuals not only suffer from consistent wheezing and coughing but are also believed to be more prone to serious lung infections that result in bronchitis and pneumonia. However, little is known about the influence of asthma on host mucosal immunity. Here we show that antibody responses during secondary heterologous influenza infections are suboptimal and that this is responsible for the increased mortality in asthmatic mice from viral infections. Understanding the mechanism of increased susceptibility will aid in developing new antiviral therapies for asthmatic patients.

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Section: Discussionmentioning

confidence: 84%

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Furuya

Roberts

Hurteau

et al. 2014

J Virol

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“…Asthmatic patients can also suffer from bacterial complications, and increased susceptibility to bacterial infection is observed in mouse models of allergic airway disease. As with viral infections, this is associated with increased expression of the negative regulators such as CD200R on alveolar macrophages [35] (fig. 1).…”

Section: Mechanisms Of Susceptibility To Infectionsmentioning

confidence: 99%

Macrophage adaptation in airway inflammatory resolution

et al. 2015

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Bacterial and viral infections (exacerbations) are particularly problematic in those with underlying respiratory disease, including post-viral infection, asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. Patients experiencing exacerbations tend to be at the more severe end of the disease spectrum and are often difficult to treat. Most of the unmet medical need remains in this patient group. Airway macrophages are one of the first cell populations to encounter airborne pathogens and, in health, exist in a state of reduced responsiveness due to interactions with the respiratory epithelium and specific factors found in the airway lumen. Granulocyte-macrophage colony-stimulating factor, interleukin-10, transforming growth factor-β, surfactant proteins and signalling via the CD200 receptor, for example, all raise the threshold above which airway macrophages can be activated. We highlight that following severe respiratory inflammation, the airspace microenvironment does not automatically re-set to baseline and may leave airway macrophages more restrained than they were at the outset. This excessive restraint is mediated in part by the clearance of apoptotic cells and components of extracellular matrix. This implies that one strategy to combat respiratory exacerbations would be to retune airway macrophage responsiveness to allow earlier bacterial recognition. @ERSpublications Re-educating airway macrophages that do not reset to baseline following severe inflammation

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“…On the other hand, ALI decreased lung infection by Klebsiella pneumoniae (32), a respiratory pathogen with etiology similar to that of S. pneumoniae. OVA-induced ALI had no effect on the response to S. pneumoniae serotype 4 aerosol infection (33), although HDM-induced ALI increased lung bacterial levels due to diminished Toll-like receptor signaling (34). It is important that, in the latter study, the authors infected the animals with S. pneumoniae 3 days following the final HDM challenge, while we found that the height of ALIinduced resistance occurred 10 days following allergen challenge.…”

Section: Discussionmentioning

confidence: 49%

“…Taking the data together, it is possible that not only increased bacterial clearance but also decreased tissue injury is responsible for the enhanced survival after ALI and bacterial challenge that was observed in our study. Decreased injury could be due to reduced Toll-like receptor signaling (34) and/or heightened production of homeostatic anti-inflammatory cytokines, such as IL-10, TGF-␤1, IL-22, and amphiregulin, following ALI. Although no IL-10, IL-22, or amphiregulin was detectable on day 10 following ALI (data not shown), levels of lung TGF-␤ were significantly increased (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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...

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Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung

Cited by 60 publications

References 49 publications

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Macrophage adaptation in airway inflammatory resolution

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

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Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung

Cited by 60 publications

References 49 publications

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Asthma Increases Susceptibility to Heterologous but Not Homologous Secondary Influenza

Macrophage adaptation in airway inflammatory resolution

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

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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