Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection

Abstract

Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-gamma, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.

Temporal cross‐correlation between influenza‐like illnesses and invasive pneumococcal disease in The Netherlands

“…The one‐week lag observed between ILI and IPD through plain CCF corresponds to the lag observed at individual level 11, 46, 47. Our results are in line with those of Kuster et al 19.…”

Contribution of vaccines to our understanding of pneumococcal disease

“…It is thus the response to influenza virus (or other respiratory viruses) that down-regulates the innate immune response to the pneumococcus. There are a number of hypotheses for the mechanism of downregulation, including induction of gammainterferon leading to downregulation of the MARCO receptor in alveolar macrophages [52], and type 1 interferon-mediated reduction in the production of chemo-attractants for neutrophils [53]. Influenza infection also increases susceptibility to pneumococcal acquisition in ferrets [54] and the role of respiratory viruses may be critical to the transmission of the pneumococcus in humans, with observations over the past 50 years suggesting enhanced isolation of pneumococci from individuals with symptomatic upper respiratory tract infections [55][56][57].…”

Dynamics of Increasing IFN-γ Exposure on Murine MH-S Cell-Line Alveolar Macrophage Phagocytosis ofStreptococcus pneumoniae

“…During the early course of an infection, IL-12 and IL-18 promote IFN-g secretion (Munder and others 2001) from numerous antigen-presenting cells, including monocytes/ macrophage, dendritic cells, and natural killer cells, and later in infection from CD4 + T helper and CD8 + cytotoxic lymphocytes (Otani and others 1999;Schroder and others 2004). Once secreted, the type II IFN aids in leukocyte recruitment, upregulation of antigen presentation by both MHC class I and II, differentiation of multiple cell types, and enhances or reduces macrophage function (Schroder and others 2004;Sun and Metzger 2008). While IFN-g (originally termed ''macrophage activating factor'') is widely known to activate macrophage activity, it is also known to reduce alveolar macrophage (AM) detection and phagocytosis of the encapsulated Gram-positive bacterial pathogen Streptococcus pneumonia (the pneumococcus) (Mosser and Handman 1992;Chroneos and Shepherd 1995;Sun and Metzger 2008).…”

“…Once secreted, the type II IFN aids in leukocyte recruitment, upregulation of antigen presentation by both MHC class I and II, differentiation of multiple cell types, and enhances or reduces macrophage function (Schroder and others 2004;Sun and Metzger 2008). While IFN-g (originally termed ''macrophage activating factor'') is widely known to activate macrophage activity, it is also known to reduce alveolar macrophage (AM) detection and phagocytosis of the encapsulated Gram-positive bacterial pathogen Streptococcus pneumonia (the pneumococcus) (Mosser and Handman 1992;Chroneos and Shepherd 1995;Sun and Metzger 2008). In mice, this reduction in phagocytic activity occurs within hours of IFN-g treatment and is mediated, at least in part, by a reduction in expression of the class A scavenger receptor MARCO (macrophage receptor with collagenous structure) on the surface of the AM (Sun and Metzger 2008), important for pneumococcal surveillance and clearance (Arredouani and others 2004).…”

“…While IFN-g (originally termed ''macrophage activating factor'') is widely known to activate macrophage activity, it is also known to reduce alveolar macrophage (AM) detection and phagocytosis of the encapsulated Gram-positive bacterial pathogen Streptococcus pneumonia (the pneumococcus) (Mosser and Handman 1992;Chroneos and Shepherd 1995;Sun and Metzger 2008). In mice, this reduction in phagocytic activity occurs within hours of IFN-g treatment and is mediated, at least in part, by a reduction in expression of the class A scavenger receptor MARCO (macrophage receptor with collagenous structure) on the surface of the AM (Sun and Metzger 2008), important for pneumococcal surveillance and clearance (Arredouani and others 2004). Reduced phagocytosis may also be mediated by reductions in C-type lectin receptors on the macrophage cell surface, important for detection and killing of S. pneumonia (Chroneos and Shepherd 1995).…”