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

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Review

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

David J Morgan et al. Front Immunol.

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.

Keywords: apoptotic cells; bacteria; innate immunity; lung; macrophage; matrix; training; virus.

Figures

Figure 1
Figure 1
Inhibitory regulation of alveolar macrophages by the airway epithelium. Strict regulation of macrophage activation is required for homeostatic control of the general lung environment. As alveolar macrophages are under constant exposure to airborne endotoxins hypo-responsiveness is required for normal airway macrophage function. This is contributed through a number of downstream pathways triggered by airway epithelial cells production of IL-10, TGFβ, CD200, and surfactant proteins (SPA and SPD) and these reduce pro-inflammatory signaling and phagocytosis in airway macrophages via their respective cell surface receptors. The cascade of downstream inhibitory pathways to suppress macrophage activation are summarized elsewhere. Adapted from (35).
Figure 2
Figure 2
Clearance of apoptotic cells impairs anti-bacterial immunity. Removal of apoptotic cells requires their recognition by specialized receptors on phagocytic cells, including macrophages. In the presence of healthy cells (top left) Phosphatidylserine (PtdSer) is on the inner leaflet of the membrane. Local macrophages do not recognize them and therefore are able to signal through Toll-like receptors (TLR) unimpeded, resulting in the proinflammatory cytokine response. This optimal response is able to contain and clear bacterial infections (shown in red ovals). However, upon programmed cell death, PtdSer and a variety of other proteins are translocated to the outside of the cell membrane (top right). Macrophages recognize these exposed proteins via specific receptors (bottom right). These receptors facilitate apoptotic cell recognition and engulfment (known as efferocytosis) however, during efferocytosis macrophages are unable to respond to bacteria leading to their outgrowth (bottom right).
Figure 3
Figure 3
Fast and limited immunity is good. A time limited burst of inflammation limits bystander tissue damage, which in turn limits the extent of tissue repair. This leads to less impairment of anti-bacterial immunity and so a secondary bacterial infection is cleared. A virulent pathogen, or one that isn't cleared quickly, causes prolonged bystander tissue damage leading to a lengthy period of repair; the processes of which are anti-inflammatory. A subsequent bacterial infection is ignored and grows exponentially. Ultimately, innate immunity is activated when the bacterial load is excessive causing deleterious consequences.

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