Innate Immune Cell Suppression and the Link With Secondary Lung Bacterial Pneumonia

Abstract

Secondary infections arise as a consequence of previous or concurrent conditions and occur in the community or in the hospital setting. The events allowing secondary infections to gain a foothold have been studied for many years and include poor nutrition, anxiety, mental health issues, underlying chronic diseases, resolution of acute inflammation, primary immune deficiencies, and immune suppression by infection or medication. Children, the elderly and the ill are particularly susceptible. This review is concerned with secondary bacterial infections of the lung that occur following viral infection. Using influenza virus infection as an example, with comparisons to rhinovirus and respiratory syncytial virus infection, we will update and review defective bacterial innate immunity and also highlight areas for potential new investigation. It is currently estimated that one in 16 National Health Service (NHS) hospital patients develop an infection, the most common being pneumonia, lower respiratory tract infections, urinary tract infections and infection of surgical sites. The continued drive to understand the mechanisms of why secondary infections arise is therefore of key importance.

The role of macrophages in the resolution of inflammation

“…In the active model, macrophages secrete factors that actively promote tissue repair. These include antiinflammatory molecules (IL-10 and TGF-β), growth factors (VEGF, PDGFA), matrix metalloproteinases (MMP-8, -10, -28), and osteopontin (65)(66)(67). Macrophages are also thought to be the major source of resolvins, protectins, and maresins, long-chain fatty acid-derived lipid mediators shown to drive the resolution of tissue injury in a wide variety of pathologies (68).…”

Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies

“…Seasonal influenza alone typically leads to a rather transient illness in healthy individuals. However, seasonal and pandemic influenza can predispose the high‐risk individuals to severe secondary bacterial superinfection caused often by Streptococcus pneumoniae ( S. pneumoniae ), Staphylococcus aureus ( S. aureus ), or Haemophilus influenzae 18,24 . Such bacterial superinfection often occurs both in humans and experimental animals within 7–14 days post‐infection when influenza virus has been cleared from the lung.…”

“…It has been observed in animal models that such a state of innate immune tolerance following influenza can last for weeks or even months long after viral clearance, 25 thus representing a state of innate immune memory. Inducibility of innate immune tolerance is not limited only to influenza virus as some other respiratory viral pathogens such as respiratory syncytial virus are capable of the same 18 . As a result of innate immune tolerance by prior influenza exposure, the initial innate immune responses to bacterial superinfection are suppressed, which in turn leads to uncontrolled bacterial replication and the untimely and exaggerated innate cellular responses and immunopathology in the lung 18,24,26,27 .…”

“…1). 13–18 Microglial cells in the brain developed an either trained or tolerized memory phenotype in response to a single and repeated systemic LPS exposure, respectively 17 . Airway Mϕs in the lung developed a long‐term memory following an acute episode of respiratory adenoviral infection and contribute to robust anti‐bacterial TII‐mediated protection 13 .…”

“…Airway Mϕs in the lung developed a long‐term memory following an acute episode of respiratory adenoviral infection and contribute to robust anti‐bacterial TII‐mediated protection 13 . On the other hand, the memory airway Mϕs induced by influenza infection become hypo‐reactive to secondary bacterial infection in the lung 18 . Phenotypic changes associated with innate immune memory have also been seen in non‐hematopoietic innate cells including mucosal epithelial cells or their progenitor cells in the skin and lung airway 19–21 .…”