Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice
Shigeki Nakamura1, Kimberly M Davis, Jeffrey N Weiser
1Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6076, USA.
Abstract:
Pneumococcal infection of the respiratory tract is often secondary to recent influenza virus infection and accounts for much of the morbidity and mortality during seasonal and pandemic influenza. Here, we show that coinfection of the upper respiratory tract of mice with influenza virus and pneumococcus leads to synergistic stimulation of type I IFNs and that this impairs the recruitment of macrophages, which are required for pneumococcal clearance, due to decreased production of the chemokine CCL2. Type I IFN expression was induced by pneumococcal colonization alone. Colonization followed by influenza coinfection led to a synergistic type I IFN response, resulting in increased density of colonizing bacteria and susceptibility to invasive infection. This enhanced type I IFN response inhibited production of the chemokine CCL2, which promotes the recruitment of macrophages and bacterial clearance. Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin. Indeed, the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin. We therefore propose that the synergistic stimulation of type I IFN production during concurrent influenza virus and pneumococcal infection leads to increased bacterial colonization and suggest that this may contribute to the higher rates of disease associated with coinfection in humans.
Insights
Coinfection with influenza and pneumococcus synergistically boosts type I interferons (IFNs), impairing macrophage recruitment and increasing bacterial colonization. This IFN response hinders chemokine CCL2 production, crucial for clearing pneumococcal infections.
Area of Science:
- Immunology
- Microbiology
- Respiratory Infections
Background:
- Pneumococcal infections frequently follow influenza, contributing significantly to respiratory illness severity and mortality.
- Understanding the interplay between influenza and pneumococcal infections is critical for public health.
Purpose of the Study:
- To investigate the immunological mechanisms underlying enhanced pneumococcal colonization during concurrent influenza virus infection.
- To elucidate the role of type I interferons (IFNs) and chemokine signaling in coinfection outcomes.
Main Methods:
- Coinfection models in mice using influenza virus and Streptococcus pneumoniae.
- Analysis of type I IFN responses, chemokine production (CCL2), and macrophage recruitment.
- Assessment of bacterial colonization and susceptibility to invasive infection in genetically modified mice (Nod2, type I IFN receptor deficient) and with modified bacteria (pneumolysin deficient).
Main Results:
- Concurrent influenza infection synergistically enhanced type I IFN production induced by pneumococcal colonization.
- This synergistic IFN response led to increased pneumococcal colonization and susceptibility to invasive disease.
- The elevated type I IFN response suppressed the production of chemokine CCL2, impairing macrophage recruitment and bacterial clearance.
- Nod2 and pneumolysin were identified as key mediators in the pneumococcus-induced CCL2 production, and their absence or blockade of the type I IFN receptor prevented enhanced colonization.
Conclusions:
- Synergistic type I IFN stimulation during coinfection impairs host defense by reducing CCL2-mediated macrophage recruitment.
- This mechanism contributes to increased bacterial load and disease severity in coinfected individuals.
- Targeting type I IFN pathways or enhancing chemokine signaling could be potential therapeutic strategies.
More Related Videos
09:12Characterization of Inflammatory Responses During Intranasal Colonization with Streptococcus pneumoniae
Published on: January 17, 2014
10:47Using Bioluminescent Imaging to Investigate Synergism Between Streptococcus pneumoniae and Influenza A Virus in Infant Mice
Published on: April 14, 2011
Related Concept Videos
02:22The Colonization of Land
02:40The Eukaryotic Promoter Region
02:40The Eukaryotic Promoter Region
01:30Pneumonia I: Introduction
Risk Factors
Various factors influence the likelihood of developing pneumonia. Age plays a crucial role, with infants, children under two, and individuals over 65 at increased risk due to their...
01:29Pneumonia II: Pathophysiology
00:50What are Viruses?