Type I Interferon Protects against Pneumococcal Invasive Disease by Inhibiting Bacterial Transmigration across the Lung

Abstract

Streptococcus pneumoniae infection is a leading cause of bacterial pneumonia, sepsis and meningitis and is associated with high morbidity and mortality. Type I interferon (IFN-I), whose contribution to antiviral and intracellular bacterial immunity is well established, is also elicited during pneumococcal infection, yet its functional significance is not well defined. Here, we show that IFN-I plays an important role in the host defense against pneumococci by counteracting the transmigration of bacteria from the lung to the blood. Mice that lack the type I interferon receptor ( Ifnar1 ^−/−) or mice that were treated with a neutralizing antibody against the type I interferon receptor, exhibited enhanced development of bacteremia following intranasal pneumococcal infection, while maintaining comparable bacterial numbers in the lung. In turn, treatment of mice with IFNβ or IFN-I-inducing synthetic double stranded RNA (poly(I:C)), dramatically reduced the development of bacteremia following intranasal infection with S. pneumoniae. IFNβ treatment led to upregulation of tight junction proteins and downregulation of the pneumococcal uptake receptor, platelet activating factor receptor (PAF receptor). In accordance with these findings, IFN-I reduced pneumococcal cell invasion and transmigration across epithelial and endothelial layers, and Ifnar1 ^−/− mice showed overall enhanced lung permeability. As such, our data identify IFN-I as an important component of the host immune defense that regulates two possible mechanisms involved in pneumococcal invasion, i.e. PAF receptor-mediated transcytosis and tight junction-dependent pericellular migration, ultimately limiting progression from a site-restricted lung infection to invasive, lethal disease.

Author Summary

Streptococcus pneumoniae infection is a leading cause of bacterial pneumonia and invasive diseases such as sepsis and meningitis, which are associated with high morbidity and mortality. Here we identified type I Interferons (IFN-I) as critical mediators that prevent the progression of a local lung infection with S. pneumoniae to invasive disease. We found that mice lacking the receptor for IFN-I, or which received antibodies that interfere with receptor activation, showed increased development of bacteremia upon lung infection with S. pneumoniae. Treating mice, or cell lines, with IFN-I protected against bacterial migration across epithelial and endothelial cell barriers, correlating with increased expression of tight junction proteins, which enhance the lung's barrier function, and reduced surface expression levels of platelet activating factor receptor, a host receptor known to be hijacked by bacteria for migration across the lung/blood and blood/brain barriers. Together, our results identify IFN-I as an important component of the host immune defense against invasion from a gram-positive, extracellular bacterium, possibly reflecting a general mechanism for the regulation of epithelial and endothelial barrier function that is critical for protection from pathogen invasion.