New insights into the pathogenesis of invasive pulmonary aspergillosis : real time imaging of hypoxia and inflammatio

Ref ID: 19615

Author:

O Ibrahim-Granet1*, A Rekiki1, A Savers1, M Parlato1, M Brock2, JM Cavaillon1

Author address:

1Unité de Recherche Cytokines & Inflammation, Institut Pasteur, Paris, France
2Research Group Microbial Biochemistry and Physiology, Hans-Knoell-Institute, Jena, Germany

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Aspergillus fumigatus, is responsible for relevant diseases especially in immunocompromised
individuals. Among these, life-threatening invasive pulmonary aspergillosis (IPA) results in mortality
rates ranging from 30-90%. While investigating the role of immune effector cells in host defense
against A. fumigatus using a bioluminescent A. fumigatus reporter strain, we recently showed that
one day post-infection lungs from cortisone acetate-treated mice displayed severe tissue necrosis
and hypoxia (Brock et al 2008, Ibrahim-Granet O et al 2010, Galiger et al 2013). Development of
hypoxia was confirmed by Grahl et al in 2011 using the hypoxia marker pimonidazole hydrochloride
on lungs sections from euthanized mice with IPA. In this study we focused on the in vivo real-time
monitoring of hypoxia and inflammation within the lungs of mice from three immunologically distinct
murine models of invasive pulmonary aspergillosis, i. e. cortisone acetate versus cyclophospahmide
treatment versus CXCR2 knock- out mice (Ibrahim-Granet et al BMC 2010).
Methods:
To monitor disease progression, hypoxia and inflammation we used bioluminescence imaging and
fluorescence molecular tomography systems (Perkin Elmer) on mice infected with the luminescent
A. fumigatus strain. Here, (i) fungal growth was quantified by bioluminescence, (ii) hypoxia was
quantified by the cell surface expression of carbonic anhydrase (CAIX) and (iii) inflammation
was determined through the pan cathepsin proteases known to be produced by inflammatory
cells. In addition, inflammation was investigated from lung tissues homogenates by studying the
inflammatory cytokine patterns by ELISA.
Results:
Three days following infection hypoxia was detected under all infectious conditions regardless the
immune status of mice. Even immunocompetent mice developed hypoxia levels five times higher
than mock-infected (control) animals although no invasive aspergillosis developed. However,
hypoxia was most pronounced in susceptible CXCR2 KO mice (28 times higher than control)
followed by corticosteroid and cyclophosphamide treated animals. In the CXCR2 KO mice, the
high level of hypoxia is associated with an overwhelming inflammatory cytokines levels in the lungs
homogenate. Regarding the cathepsin level, in immunocompetent animals, cathepsin was hardly
detectable within the lungs of the mice. However, in corticosteroid animals the presence of cathepsin
was more pronounced (11 times compared to control). Interestingly, in CXCR2 KO, showing the
highest level of hypoxia, the presence of cathepsin was only moderate (3 times compared to control).
This indicates that the pan cathepsin proteases activity is not necessarily linked to the severity of the
infection and the role of these proteases in the clearance of the infection needs further investigations.
Conclusion:
This is the first study that correlates hypoxia with fungal growth in real-time from in vivo models
of murine IPA. Importantly our data brings new insights on the contribution of hypoxia to lung
inflammation during fungal infection. Impact of hypoxia on the innate immune system during
invasive pulmonary aspergillosis has to be investigated.

Abstract Number: 140

Conference Year: 2014

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

New link: NULL

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