Impaired interferon-gamma responses, increased interleukin-17 expression, and a tumor necrosis factor-alpha transcriptional program in invasive aspergillosis.
BACKGROUND
Invasive aspergillosis (IA) is the most common cause of death associated with fungal infection in the developed world. Historically, susceptibility to IA has been associated with prolonged neutropenia; however, IA has now become a major problem in patients on calcineurin inhibitors and allogenic hematopoietic stem cell transplant patients following engraftment. These observations suggest complex cellular mechanisms govern immunity to IA.


METHODS
To characterize the key early events that govern outcome from infection with Aspergillus fumigatus, we performed a comparative immunochip microarray analysis of the pulmonary transcriptional response to IA between cyclophosphamide-treated mice and immunocompetent mice at 24 h after infection.


RESULTS
We demonstrate that death due to infection is associated with a failure to generate an incremental interferon-gamma response, increased levels of interleukin-5 and interleukin-17a transcript, coordinated expression of a network of tumor necrosis factor-alpha-related genes, and increased levels of tumor necrosis factor-alpha. In contrast, clearance of infection is associated with increased expression of a number genes encoding proteins involved in innate pathogen clearance, as well as apoptosis and control of inflammation.


CONCLUSIONS
This first organ-level immune response transcriptional analysis for IA has enabled us to gain new insights into the mechanisms that govern fungal immunity in the lung.
Armstrong-James
Darius P H
DP
Guys and St. Thomas' Hospital National Health Service Foundation Trust and Department of Microbiology, Imperial College London, London, United Kingdom.
Turnbull
Suzy A
SA
Teo
Ian
I
Stark
Jaroslav
J
Rogers
Nicola J
NJ
Rogers
Thomas R F
TR
Bignell
Elaine
E
Haynes
Ken
K
D000818:Animals; D018076:DNA, Complementary; D005786:Gene Expression Regulation / Q000276:immunology; D016867:Immunocompromised Host; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D055732:Pulmonary Aspergillosis / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma