Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax.
BACKGROUND
Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro.


RESULTS
We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling.


CONCLUSIONS
In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality.
Gold
Jeffrey A
JA
Division of Pulmonary and Critical Care Medicine, Oregon Health and Sciences University, Portland, Oregon, United States of America. goldje@ohsu.edu
Hoshino
Yoshihiko
Y
Jones
Marcus B
MB
Hoshino
Satomi
S
Nolan
Anna
A
Weiden
Michael D
MD
D000280:Administration, Inhalation; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000401:mortality; D001408:Bacillus anthracis / Q000276:immunology / Q000472:pathogenicity; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D007378:Interleukins / Q000097:blood / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013171:Spores, Bacterial / Q000276:immunology; D015996:Survival Rate
D016898:Interferon-alpha; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse
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