Abstract
Excessive neutrophilic inflammation can contribute to the pathogenesis of pneumonia. Whilst anti-inflammatory therapies such as corticosteroids are used to treat excessive inflammation, they do not selectively target neutrophils and may compromise antimicrobial or antiviral defences. In this study, neutrophil trafficking was targeted with a granulocyte-colony stimulating factor receptor monoclonal antibody (G-CSFR mAb) during Streptococcus pneumoniae (serotype 19F) or influenza A virus (IAV, strain HKx31) lung infection in mice. Firstly, we demonstrated that neutrophils are indispensable for the clearance of S. pneumoniae from the airways using an anti-Ly6G monoclonal antibody (1A8 mAb), as the complete inhibition of neutrophil recruitment markedly compromised bacterial clearance. Secondly, we demonstrated that G-CSF transcript lung levels were significantly increased during pneumococcal infection. Prophylactic or therapeutic administration of G-CSFR mAb significantly reduced blood and airway neutrophil numbers by 30–60% without affecting bacterial clearance. Total protein levels in the bronchoalveolar lavage (BAL) fluid (marker for oedema) was also significantly reduced. G-CSF transcript levels were also increased during IAV lung infection. G-CSFR mAb treatment significantly reduced neutrophil trafficking into BAL compartment by 60% and reduced blood neutrophil numbers to control levels in IAV-infected mice. Peak lung viral levels at day 3 were not altered by G-CSFR therapy, however there was a significant reduction in the detection of IAV in the lungs at the day 7 post-infection phase. In summary, G-CSFR signalling contributes to neutrophil trafficking in response to two common respiratory pathogens. Blocking G-CSFR reduced neutrophil trafficking and oedema without compromising clearance of two pathogens that can cause pneumonia.
Highlights
Excessive neutrophilic inflammation can contribute to the pathogenesis of pneumonia
In the low inoculum model, S. pneumoniae was effectively cleared in the lungs, suppression of neutrophil trafficking with 1A8 mAb resulted in a high bacterial burden in the lungs at day 2 post S. pneumoniae infection (Fig. 2A)
We have shown that G-CSF receptor (G-CSFR) signalling contributes to neutrophil granulopoiesis and trafficking into the airways in response to two common respiratory pathogens, namely Streptococcus pneumoniae and influenza A virus
Summary
Excessive neutrophilic inflammation can contribute to the pathogenesis of pneumonia. Whilst antiinflammatory therapies such as corticosteroids are used to treat excessive inflammation, they do not selectively target neutrophils and may compromise antimicrobial or antiviral defences. Neutrophil trafficking was targeted with a granulocyte-colony stimulating factor receptor monoclonal antibody (G-CSFR mAb) during Streptococcus pneumoniae (serotype 19F) or influenza A virus (IAV, strain HKx31) lung infection in mice. Blocking G-CSFR reduced neutrophil trafficking and oedema without compromising clearance of two pathogens that can cause pneumonia. The influx of www.nature.com/scientificreports neutrophils into the airways is normally self-limiting, as short-lived neutrophils undergo apoptosis and are subsequently phagocytised by alveolar and exudative macrophages in the lungs Despite their critical role in pathogen containment, excessive neutrophil activation will generate reactive oxygen species (ROS) and release a variety of proteases that can degrade extracellular matrix, resulting in acute lung injury and pulmonary oedema. G-CSFR mAb therapy during influenza infection in mice did not cause neutropenia or compromise viral clearance, it was not established whether viral-induced blood neutrophilia and neutrophil trafficking into the lungs were reduced. We have assessed whether G-CSFR mAb can safely reduce neutrophilic lung inflammation and injury/oedema during acute IAV infection in mice
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