Hypoxia inducible factor 1 alpha is required for pulmonary innate immune response to Aspergillus fumigatus

Ref ID: 19604

Author:

KM Shepardson1*, A Jhingran2, JJ Obar3, TM Hohl2, RA Cramer1

Author address:

1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, USA
2Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA
3Department of Immunology and Infectious Diseases, Montana State Univers

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
While much effort is being placed in identifying new antifungal drug targets and compounds, an
alternative and increasingly important area of investigation is finding therapies that work at increasing
the host response and defense to fungal infections in immune compromised hosts. Recent studies
have implicated a role for hypoxia inducible factor 1 (HIF1α ) in the regulation of inflammation and
host defense responses to microbial pathogens. Thus, the goal of my studies is to define the role of
HIF1α in pulmonary immune responses to A. fumigatus.
Methods:
We utilized the glucocorticoid model of immunosuppression by triamcinolone in CD-1 mice to
determine the involvement of HIF1α in the susceptibility to fungal infection by A. fumigatus. The
HIF1α agonist L-mimosine was used in an ex vivo macrophage model as a treatment for glucocorticoid
suppression, as measured by HIF1α protein and XTT-fungal damage. The in vivo involvement of
HIF1α for clearance and defense against A. fumigatus was determined using a myeloid-specific
lysozyme-M cre-recombinase knockout mouse of HIF1α (HIF-KO) compared to littermate controls.
We used flow cytometry, fungal burden, neutrophil migration and luminex analysis to investigate
HIF1α ’s role in pulmonary control of two A. fumigatus strains with different inflammatory profiles:
wild type CEA10 (CBS144.89) and null 916;orlA mutant.
Results:
We observed that A. fumigatus could stabilize HIF1α protein in macrophages, independent
of oxygen availability, and in lungs of infected mice. This protein stabilization of HIF1α was
prevented by treatment of macrophages and mice with glucocorticoids, corresponding to a decrease
in the antifungal activity of the macrophages. Therapeutic treatment of glucocorticoid-suppressed
macrophages with a HIF1α agonist partially restored their antifungal activity.
Utilizing the HIF-KO mice, we observed that HIF1α is required for survival, fungal clearance,
neutrophil recruitment, and inflammatory responses early during infection with the inflammatory
strain CEA10. The early neutrophil recruitment defect at 8 and 12hr post infection in the HIF-KO
mice was demonstrated to be due to a defective cytokine response, as ex vivo neutrophils were able
to respond and migrate in the presence of infected littermate BALFs but not infected HIF-KO BALF.
Cytokine analysis of the BALF from infected littermate and HIF-KO mice found decreased levels
of KC. Addition of KC to levels found in littermate BALF into the HIF-KO BALF significantly
restored the migration defect. Additionally, the hyper-inflammatory strain 916;orlA was able to restore
the neutrophil defect in the HIF-KO mice, further supporting a signaling defect.
Conclusion:
Our data suggest that myeloid HIF1α is required for initiating the correct inflammatory signal and
responses in order to control and clear A. fumigatus infection. The data strongly suggest that the
timing of this response is critical for determining the outcome of the infection. Ongoing studies
will determine whether the in vivo restoration of the signaling defect in HIF-KO mice will improve
recruitment and survival. Additionally, this work supports the strategy of utilizing HIF1α as a
therapeutic target in specific immunosuppressed populations with fungal infections. Future studies
will seek to further define the mechanisms by which HIF1α helps mediate antifungal immune
responses in the lung.

Abstract Number: 129

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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