Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice
Shigeki Nakamura, … , Kimberly M. Davis, Jeffrey N. Weiser
Shigeki Nakamura, … , Kimberly M. Davis, Jeffrey N. Weiser
Published August 15, 2011
Citation Information: J Clin Invest. 2011;121(9):3657-3665. https://doi.org/10.1172/JCI57762.
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Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice

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.

Authors

Shigeki Nakamura, Kimberly M. Davis, Jeffrey N. Weiser

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Figure 3

Coinfection with influenza virus induces synergistic IFN-β expression and enhances pneumococcal nasopharyngeal colonization.

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Coinfection with influenza virus induces synergistic IFN-β expression an...
(A) Experimental protocol for coinfection model. WT mice were given an intranasal inoculation with S. pneumoniae (P1121 strain, 107 CFU) or PBS, followed a day later by an intranasal inoculation with influenza virus (PR8 strain, 1,000 TCID50) or PBS. (B) Mice infected with PR8 strain were monitored for body weight (white squares, P1121+PR8; black diamonds, PR8 alone). (C) Titer of influenza virus in singly infected and coinfected mice was calculated based on viral RNA detected in URT lavages (black bars) and lung homogenates (white bars). (D) H&E staining of representative lung tissue sections from mice infected with S. pneumoniae alone and coinfected with influenza virus. Original magnification, ×200. Horizontal lines indicate mean values. (E) The density of pneumococcal colonization was measured in singly infected and coinfected mice at day 7. (F) Levels of IFN-β mRNA in URT lavages from singly infected and coinfected mice were examined by qRT-PCR. (G) Numbers of F4/80+CD45+ macrophages and Ly6G+CD45+ neutrophils recruited to the URT were analyzed by flow cytometry from uninfected, singly infected, and coinfected mice. (H) Levels of Ccl2 and KC mRNA in URT lavages from singly infected and coinfected mice as determined by qRT-PCR. (I) Survival rates of mice infected with serotype 6A pneumococcus alone (squares; n = 20) and serotype 6A pneumococcus coinfected with PR8 (diamonds; n = 20). Values represent mean ± SD. *P < 0.05, **P < 0.01.