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Review
. 2018 Oct 16:9:2345.
doi: 10.3389/fimmu.2018.02345. eCollection 2018.

Resolving Viral-Induced Secondary Bacterial Infection in COPD: A Concise Review

Hao Wang  1 , Desiree Anthony  1 , Stavros Selemidis  1 , Ross Vlahos  1 , Steven Bozinovski  1
Affiliations
Review

Resolving Viral-Induced Secondary Bacterial Infection in COPD: A Concise Review

Hao Wang et al. Front Immunol. .

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline. Pathological inflammation is worsened by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens. Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium. Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes. This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria. The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage. AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA). SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils. Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1. We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria.

Keywords: COPD-chronic obstructive pulmonary disease; co-infection; exacerbation; influenza (flu); pneumococcus (Streptococcus pneumoniae); resolvin D1 (RvD1); secondary infection; serum amyloid A (SAA).

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Figures

Figure 1
Figure 1
Proposed therapeutic actions of AT-RvD1 during acute exacerbations in chronically infected COPD patients. Excessive inflammation and ROS are a characteristic feature of the COPD lung microenvironment. Excessive ROS directly impairs macrophage function preventing efficient phagocytosis of potentially pathogenic bacteria and efferocytosis (removal of dying neutrophils). This has deleterious effects on mucosal immunity and permits the establishment of chronic bacterial infection of the lower airways. Upon exposure to a newly acquired viral infection, which is a common trigger for AECOPD, the virus permits the further outgrowth of bacteria causing a bacterial super-infection in the lungs. SAA is significantly increased during co-infections and stimulates neutrophilic inflammation via FPR2/ALX-dependent mechanisms. Excessive neutrophilic inflammation can drive mucus hypersecretion and degrade anti-microbial peptides in the airways. We propose that the alternative FPR2/ALX agonist, AT-RvD1 can therapeutically intervene at critical pathological pathways that lead to bacterial super-infections. AT-RvD1 facilitates the resolution of inflammation during co-infections by improving the phagocytic clearance of bacteria and efferocytosis of apoptotic neutrophils in the lungs. It also potently suppresses neutrophil migration, thereby limiting tissue damage, mucus secretion and anti-microbial peptide degradation caused by ongoing inflammation. AT-RvD1 may also reduce neuroinflammation consequent to serious lung co-infections as brain microglia are activated by SAA in manner that is suppressed by AT-RvD1.
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