Influenza-induced expression of indoleamine 2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia.
BACKGROUND
Airway infection with influenza virus induces local expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which has been shown to enhance inflammatory mediator responses in vitro. Because secondary pneumococcal infections occurring shortly after recovery from influenza are associated with enhanced inflammatory responses, we hypothesized that IDO activity contributes to the enhanced response to bacterial challenges in mice previously infected with influenza virus.


METHODS
On day 14 after influenza virus infection (with strain A/PR/8/34), C57Bl/6 mice were intranasally inoculated with 1 x 10(4) colony-forming units of S. pneumoniae (serotype 3). Matrix-driven delivery pellets that contained 70 mg of the IDO inhibitor 1-methyl-DL-tryptophan (MeTrp) released over a period of 7 days were subcutaneously implanted 48 h before pneumococcal infection.


RESULTS
MeTrp treatment resulted in a 20-fold reduction in pneumococcal outgrowth 48 h after bacterial inoculation. Remarkably, pulmonary levels of interleukin-10 and tumor necrosis factor-alpha were significantly reduced in mice treated with MeTrp.


CONCLUSIONS
Our data suggest that IDO expression during influenza virus infection alters the inflammatory response and facilitates the outgrowth of pneumococci during secondary bacterial pneumonia.
van der Sluijs
Koenraad F
KF
Department of Pulmonology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. kvandersluijs@amc.uva.nl
Nijhuis
Monique
M
Levels
Johannes H M
JH
Florquin
Sandrine
S
Mellor
Andrew L
AL
Jansen
Henk M
HM
van der Poll
Tom
T
Lutter
René
R
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D009980:Influenza A virus; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000201:enzymology* / Q000276:immunology*; D011018:Pneumonia, Pneumococcal / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000254:growth & development* / Q000276:immunology; D016019:Survival Analysis; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014364:Tryptophan